bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒09‒08
63 papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. "Glycans in Trained Immunity: Educators of innate immune memory in homeostasis and disease".
  2. Innate immune sensing of cell death in disease and therapeutics.
  3. The airway mycobiome and interactions with immunity in health and chronic lung disease.
  4. Trained immunity across organs.
  5. Epigenetic regulation of macrophage activation in chronic obstructive pulmonary disease.
  6. Lung microbiota: implications and interactions in chronic pulmonary diseases.
  7. The role of trained immunity in sepsis.
  8. A Comprehensive Review Exploring the Protective Role of Specific Commensal Gut Bacteria against Salmonella.
  9. Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity.
  10. Microbiome-Mucosal Immunity Nexus: Driving Forces in Respiratory Disease Progression.
  11. Tissue resident cells differentiate S. aureus from S. epidermidis via IL-1β following barrier disruption in healthy human skin.
  12. Exacerbation of influenza virus induced lung injury by alveolar macrophages and its suppression by pyroptosis blockade in a human lung alveolus chip.
  13. The role of lipids in regulating macrophage antifungal immunity.
  14. Mechanism of staphylococcal resistance to clinically relevant antibiotics.
  15. α-Hemolysin from Staphylococcus aureus Changes the Epigenetic Landscape of Th17 Cells.
  16. Role of Lipopolysaccharides in the Inflammation and Pyroptosis of Alveolar Epithelial Cells in Acute Lung Injury and Acute Respiratory Distress Syndrome.
  17. Postbiotic impact on host metabolism and immunity provides therapeutic potential in metabolic disease.
  18. A quantitative approach to measure and predict microbiome response to antibiotics.
  19. How a bacterial immune system gets taken apart.
  20. MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.
  21. Potential Contributions of Human Endogenous Retroviruses in Innate Immune Memory.
  22. CD4 + T cells recruit, then engage macrophages in cognate interactions to clear Mycobacterium tuberculosis from the lungs.
  23. Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.
  24. BCG immunization induced KLRG1+ NK cells show memory-like responses to mycobacterial and HIV antigens.
  25. Myeloid C-type lectin receptors in host-pathogen interactions and glycan-based targeting.
  26. Survival of Probiotic Bacterial Cells in the Upper Gastrointestinal Tract and the Effect of the Surviving Population on the Colonic Microbial Community Activity and Composition.
  27. YjbH contributes to staphylococcus aureus skin pathology and immune response through Agr-mediated α-toxin regulation.
  28. Lactic Acid Bacteria in the Human Oral Cavity: Assessing Metabolic Functions Relevant to Oral Health and Disease.
  29. Probiotic nucleotides increase IL-10 expression in airway macrophages to mitigate airway allergy.
  30. Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion.
  31. Pathophysiological and Clinical Potential of Human Microbiome: Microbe-based Therapeutic Insights.
  32. Cell death pathways: molecular mechanisms and therapeutic targets for cancer.
  33. Silica-induced ROS in alveolar macrophages and its role on the formation of pulmonary fibrosis via polarizing macrophages into M2 phenotype: A review.
  34. Metabolic Control of Microglia.
  35. Current Approaches to Prevent or Reverse Microbiome Dysbiosis in Chronic Inflammatory Rheumatic Diseases.
  36. scRNA-seq identifies unique macrophage population in murine model of ozone induced asthma exacerbation.
  37. VEGFR1 TK signaling protects the lungs against LPS-induced injury by suppressing the activity of alveolar macrophages and enhancing the anti-inflammatory function of monocyte-derived macrophages.
  38. Phosphatidylserine liposomes induce a phagosome acidification-dependent and ROS-mediated intracellular killing of Mycobacterium abscessus in human macrophages.
  39. Reprogramming macrophage metabolism following myocardial infarction: A neglected piece of a therapeutic opportunity.
  40. Enhanced IL-37-IL-1R8 axis is negatively associated with inflammatory and clinical severity of chronic rhinosinusitis with nasal polyps.
  41. Regulation of host metabolism and defense strategies to survive neonatal infection.
  42. Weight loss-induced adipose macrophage memory improves local Staphylococcus aureus clearance in male mice.
  43. Bystander monocytic cells drive infection-independent NLRP3 inflammasome response to SARS-CoV-2.
  44. Immunomodulation in Non-traditional Therapies for Methicillin-resistant Staphylococcus aureus (MRSA) Management.
  45. Mycobacterium tuberculosis protein Rv2652c enhances intracellular survival by inhibiting host immune responses.
  46. Oral microbiota and metabolites: key players in oral health and disorder, and microbiota-based therapies.
  47. Trained and ready - the case for an inflammatory memory for hematopoietic stem and progenitor cells in the AML niche.
  48. An ethical way forward for Indigenous microbiome research.
  49. Innate immunity in peripheral tissues is differentially impaired under normal and endotoxic conditions in aging.
  50. Dysregulated Airway Host Defense in Hyper IgE Syndrome due to STAT3 Mutations.
  51. The hidden base of the iceberg: gut peptidoglycome dynamics is foundational to its influence on the host.
  52. Quercetin Alleviates the Progression of Chronic Rhinosinusitis Without Nasal Polyps by Inhibiting Nasal Mucosal Inflammation and Epithelial Apoptosis.
  53. Friendly fire: recognition of self by the innate immune system.
  54. Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.
  55. Are you what you eat? Biggest-ever catalogue of food microbes finds out.
  56. Systemic Factors Effecting Human Beta-Defensins in Oral Cavity.
  57. [Progress on iron metabolism and ferroptosis in macrophages].
  58. Microenvironmental acidification by pneumococcal sugar consumption fosters barrier disruption and immune suppression in the human alveolus.
  59. Roles in Innate Immunity.
  60. Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.
  61. Heterogeneity of Salmonella enterica lipopolysaccharide counteracts macrophage and antimicrobial peptide defenses.
  62. Colony stimulating factor 1 receptor (Csf1r) expressing cell ablation in mafia (macrophage-specific Fas-induced apoptosis) mice alters monocyte landscape and atherosclerotic lesion characteristics.
  63. Fine particulate matter manipulates immune response to exacerbate microbial pathogenesis in the respiratory tract.
  1. Carbohydr Res. 2024 Aug 20. pii: S0008-6215(24)00224-6. [Epub ahead of print]544 109245
    "Glycans in Trained Immunity: Educators of innate immune memory in homeostasis and disease".
    Pedro Almeida, Ângela Fernandes, Inês Alves, Salomé S Pinho.
      Trained Immunity is defined as a biological process normally induced by exogenous or endogenous insults that triggers epigenetic and metabolic reprogramming events associated with long-term adaptation of innate immune cells. This trained phenotype confers enhanced responsiveness to subsequent triggers, resulting in an innate immune "memory" effect. Trained Immunity, in the past decade, has revealed important benefits for host defense and homeostasis, but can also induce potentially harmful outcomes associated with chronic inflammatory disorders or autoimmune diseases. Interestingly, evidence suggest that the "trainers" prompting trained immunity are frequently glycans structures. In fact, the exposure of different types of glycans at the surface of pathogens is a key driver of the training phenotype, leading to the reprogramming of innate immune cells through the recognition of those glycan-triggers by a variety of glycan-binding proteins (GBPs) expressed by the immune cells. β-glucan or mannose-enriched structures in Candida albicans are some of the examples that highlight the potential of glycans in trained immunity, both in homeostasis and in disease. In this review, we will discuss the relevance of glycans exposed by pathogens in establishing key immunological hubs with glycan-recognizing receptors expressed in immune cells, highlighting how this glycan-GBP network can impact trained immunity. Finally, we discuss the power of glycans and GBPs as potential targets in trained immunity, envisioning potential therapeutic applications.
    Keywords:  BCG; Candida albicans; Glycan-binding proteins; Glycans; Tolerance; Trained immunity
    DOI:  https://doi.org/10.1016/j.carres.2024.109245
  2. Nat Cell Biol. 2024 Sep 02.
    Innate immune sensing of cell death in disease and therapeutics.
    Si Ming Man, Thirumala-Devi Kanneganti.
      Innate immunity, cell death and inflammation underpin many aspects of health and disease. Upon sensing pathogens, pathogen-associated molecular patterns or damage-associated molecular patterns, the innate immune system activates lytic, inflammatory cell death, such as pyroptosis and PANoptosis. These genetically defined, regulated cell death pathways not only contribute to the host defence against infectious disease, but also promote pathological manifestations leading to cancer and inflammatory diseases. Our understanding of the underlying mechanisms has grown rapidly in recent years. However, how dying cells, cell corpses and their liberated cytokines, chemokines and inflammatory signalling molecules are further sensed by innate immune cells, and their contribution to further amplify inflammation, trigger antigen presentation and activate adaptive immunity, is less clear. Here, we discuss how pattern-recognition and PANoptosome sensors in innate immune cells recognize and respond to cell-death signatures. We also highlight molecular targets of the innate immune response for potential therapeutic development.
    DOI:  https://doi.org/10.1038/s41556-024-01491-y
  3. Oxf Open Immunol. 2024 ;5(1): iqae009
    The airway mycobiome and interactions with immunity in health and chronic lung disease.
    Orestis Katsoulis, Oliver R Pitts, Aran Singanayagam.
      The existence of commensal fungi that reside within the respiratory tract, termed the airway mycobiome, has only recently been discovered. Studies are beginning to characterize the spectrum of fungi that inhabit the human upper and lower respiratory tract but heterogeneous sampling and analysis techniques have limited the generalizability of findings to date. In this review, we discuss existing studies that have examined the respiratory mycobiota in healthy individuals and in those with inflammatory lung conditions such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. Associations between specific fungi and features of disease pathogenesis are emerging but the precise functional consequences imparted by mycobiota upon the immune system remain poorly understood. It is imperative that further research is conducted in this important area as a more detailed understanding could facilitate the development of novel approaches to manipulating the mycobiome for therapeutic benefit.
    Keywords:  chronic lung disease; fungi; immunity; mycobiome
    DOI:  https://doi.org/10.1093/oxfimm/iqae009
  4. Nat Immunol. 2024 Sep;25(9): 1509
    Trained immunity across organs.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-024-01958-y
  5. Front Immunol. 2024 ;15 1445372
    Epigenetic regulation of macrophage activation in chronic obstructive pulmonary disease.
    Feng Zhang, Yachao Cui, Tiejun Zhang, Wenguang Yin.
      Macrophages in the innate immune system play a vital role in various lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury and pulmonary fibrosis. Macrophages involved in the process of immunity need to go through a process of activation, including changes in gene expression and cell metabolism. Epigenetic modifications are key factors of macrophage activation including DNA methylation, histone modification and non-coding RNA regulation. Understanding the role and mechanisms of epigenetic regulation of macrophage activation can provide insights into the function of macrophages in lung diseases and help identification of potential therapeutic targets. This review summarizes the latest progress in the epigenetic changes and regulation of macrophages in their development process and in normal physiological states, and the epigenetic regulation of macrophages in COPD as well as the influence of macrophage activation on COPD development.
    Keywords:  COPD; DNA methylation; epigenetic regulation; histone modifications; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2024.1445372
  6. Front Cell Infect Microbiol. 2024 ;14 1401448
    Lung microbiota: implications and interactions in chronic pulmonary diseases.
    Jing Zhou, Wang Hou, Huilin Zhong, Dan Liu.
      The lungs, as vital organs in the human body, continuously engage in gas exchange with the external environment. The lung microbiota, a critical component in maintaining internal homeostasis, significantly influences the onset and progression of diseases. Beneficial interactions between the host and its microbial community are essential for preserving the host's health, whereas disease development is often linked to dysbiosis or alterations in the microbial community. Evidence has demonstrated that changes in lung microbiota contribute to the development of major chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and lung cancer. However, in-depth mechanistic studies are constrained by the small scale of the lung microbiota and its susceptibility to environmental pollutants and other factors, leaving many questions unanswered. This review examines recent research on the lung microbiota and lung diseases, as well as methodological advancements in studying lung microbiota, summarizing the ways in which lung microbiota impacts lung diseases and introducing research methods for investigating lung microbiota.
    Keywords:  chronic obstructive pulmonary disease (COPD); chronic pulmonary diseases; lung microbiota; microbial genomics; microbial metabolomics
    DOI:  https://doi.org/10.3389/fcimb.2024.1401448
  7. Front Immunol. 2024 ;15 1449986
    The role of trained immunity in sepsis.
    Wenjuan Wang, Lisi Ma, Bin Liu, Liangliang Ouyang.
      Sepsis is defined as a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection, characterized by a systemic inflammatory response to infection. The use of antibiotics, fluid resuscitation, and organ support therapy has limited prognostic benefit in patients with sepsis, and its incidence is not diminishing, which is attracting increased attention in medicine. Sepsis remains one of the most debilitating and expensive illnesses. One of the main reasons of septic mortality is now understood to be disruption of immune homeostasis. Immunotherapy is revolutionizing the treatment of illnesses in which dysregulated immune responses play a significant role. This "trained immunity", which is a potent defense against infection regardless of the type of bacteria, fungus, or virus, is attributed to the discovery that the innate immune cells possess immune memory via metabolic and epigenetic reprogramming. Here we reviewed the immunotherapy of innate immune cells in sepsis, the features of trained immunity, and the relationship between trained immunity and sepsis.
    Keywords:  immunotherapy; innate immune cells; reprogramming; sepsis; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2024.1449986
  8. Pathogens. 2024 Jul 31. pii: 642. [Epub ahead of print]13(8):
    A Comprehensive Review Exploring the Protective Role of Specific Commensal Gut Bacteria against Salmonella.
    Saloni Singh, Ok Kyung Koo.
      Gut microbiota is a diverse community of microorganisms that constantly work to protect the gut against pathogens. Salmonella stands out as a notorious foodborne pathogen that interacts with gut microbes, causing an imbalance in the overall composition of microbiota and leading to dysbiosis. This review focuses on the interactions between Salmonella and the key commensal bacteria such as E. coli, Lactobacillus, Clostridium, Akkermansia, and Bacteroides. The review highlights the role of these gut bacteria and their synergy in combating Salmonella through several mechanistic interactions. These include the production of siderophores, which compete with Salmonella for essential iron; the synthesis of short-chain fatty acids (SCFAs), which exert antimicrobial effects and modulate the gut environment; the secretion of bacteriocins, which directly inhibit Salmonella growth; and the modulation of cytokine responses, which influences the host's immune reaction to infection. While much research has explored Salmonella, this review aims to better understand how specific gut bacteria engage with the pathogen, revealing distinct defense mechanisms tailored to each species and how their synergy may lead to enhanced protection against Salmonella. Furthermore, the combination of these commensal bacteria could offer promising avenues for bacteria-mediated therapy during Salmonella-induced gut infections in the future.
    Keywords:  Salmonella; bacteria interaction; dysbiosis; gut bacteria; pathogen defense
    DOI:  https://doi.org/10.3390/pathogens13080642
  9. Sci Immunol. 2024 Sep 06. 9(99): eadp0344
    Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity.
    Anna Appios, James Davies, Sofia Sirvent, Stephen Henderson, Sébastien Trzebanski, Johannes Schroth, Morven L Law, Inês Boal Carvalho, Marlene Magalhaes Pinto, Cyril Carvalho, Howard Yuan-Hao Kan, Shreya Lovlekar, Christina Major, Andres Vallejo, Nigel J Hall, Michael Ardern-Jones, Zhaoyuan Liu, Florent Ginhoux, Sian M Henson, Rebecca Gentek, Elaine Emmerson, Steffen Jung, Marta E Polak, Clare L Bennett.
      Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.
    DOI:  https://doi.org/10.1126/sciimmunol.adp0344
  10. J Microbiol. 2024 Sep 06.
    Microbiome-Mucosal Immunity Nexus: Driving Forces in Respiratory Disease Progression.
    Young Chae Park, Soo Yeon Choi, Yunah Cha, Hyeong Won Yoon, Young Min Son.
      The importance of the complex interplay between the microbiome and mucosal immunity, particularly within the respiratory tract, has gained significant attention due to its potential implications for the severity and progression of lung diseases. Therefore, this review summarizes the specific interactions through which the respiratory tract-specific microbiome influences mucosal immunity and ultimately impacts respiratory health. Furthermore, we discuss how the microbiome affects mucosal immunity, considering tissue-specific variations, and its capacity in respiratory diseases containing asthma, chronic obstructive pulmonary disease, and lung cancer. Additionally, we investigate the external factors which affect the relationship between respiratory microbiome and mucosal immune responses. By exploring these intricate interactions, this review provides valuable insights into the potential for microbiome-based interventions to modulate mucosal immunity and alleviate the severity of respiratory diseases.
    Keywords:  Dysbiosis; Host-microbe interactions; Lung diseases; Mucosal immunity; Respiratory tract microbiome
    DOI:  https://doi.org/10.1007/s12275-024-00167-4
  11. PLoS Pathog. 2024 Aug 29. 20(8): e1012056
    Tissue resident cells differentiate S. aureus from S. epidermidis via IL-1β following barrier disruption in healthy human skin.
    Julia C Lang, Andreas Brutscher, Marcus Ehrström, Keira Melican.
      The Staphylococcus sp. are a dominant part of the human skin microbiome and present across the body. Staphylococcus epidermidis is a ubiquitous skin commensal, while S. aureus is thought to colonize at least 30% of the population. S. aureus are not only colonizers but a leading cause of skin and soft tissue infections and a critical healthcare concern. To understand how healthy human skin may differentiate commensal bacteria, such as S. epidermidis, from the potential pathogen methicillin-resistant S. aureus (MRSA), we use ex vivo human skin models that allow us to study this host-bacterial interaction in the most clinically relevant environment. Our work highlights the role of the outer stratum corneum as a protective physical barrier against invasion by colonizing Staphylococci. We show how the structural cells of the skin can internalize and respond to different Staphylococci with increasing sensitivity. In intact human skin, a discriminatory IL-1β response was identified, while disruption of the protective stratum corneum triggered an increased and more diverse immune response. We identified and localized tissue resident Langerhans cells (LCs) as a potential source of IL-1β and go on to show a dose-dependent response of MUTZ-LCs to S. aureus but not S. epidermidis. This suggests an important role of LCs in sensing and discriminating between bacteria in healthy human skin, particularly in intact skin and provides a detailed snapshot of how human skin differentiates between friend and potential foe. With the rise in antibiotic resistance, understanding the innate immune response of healthy skin may help us find ways to enhance or manipulate these natural defenses to prevent invasive infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1012056
  12. bioRxiv. 2024 Aug 16. pii: 2024.08.13.607799. [Epub ahead of print]
    Exacerbation of influenza virus induced lung injury by alveolar macrophages and its suppression by pyroptosis blockade in a human lung alveolus chip.
    Yuncheng Man, Yunhao Zhai, Amanda Jiang, Haiqing Bai, Aakanksha Gulati, Roberto Plebani, Robert J Mannix, Gwenn E Merry, Girija Goyal, Chaitra Belgur, Sean R R Hall, Donald E Ingber.
      Alveolar macrophages (AMs) are the major sentinel immune cells in human alveoli and play a central role in eliciting host inflammatory responses upon distal lung viral infection. Here, we incorporated peripheral human monocyte-derived macrophages within a microfluidic human Lung Alveolus Chip that recreates the human alveolar-capillary interface under an air-liquid interface along with vascular flow to study how residential AMs contribute to the human pulmonary response to viral infection. When Lung Alveolus Chips that were cultured with macrophages were infected with influenza H3N2, there was a major reduction in viral titers compared to chips without macrophages; however, there was significantly greater inflammation and tissue injury. Pro-inflammatory cytokine levels, recruitment of immune cells circulating through the vascular channel, and expression of genes involved in myelocyte activation were all increased, and this was accompanied by reduced epithelial and endothelial cell viability and compromise of the alveolar tissue barrier. These effects were partially mediated through activation of pyroptosis in macrophages and release of pro-inflammatory mediators, such as interleukin (IL)-1β, and blocking pyroptosis via caspase-1 inhibition suppressed lung inflammation and injury on-chip. These findings demonstrate how integrating tissue resident immune cells within human Lung Alveolus Chip can identify potential new therapeutic targets and uncover cell and molecular mechanisms that contribute to the development of viral pneumonia and acute respiratory distress syndrome (ARDS).
    DOI:  https://doi.org/10.1101/2024.08.13.607799
  13. mBio. 2024 Aug 29. e0305723
    The role of lipids in regulating macrophage antifungal immunity.
    Sophie Rouvray, Rebecca A Drummond.
      Macrophages are critical components of the antifungal immune response. Disturbance in the number or function of these innate immune cells can significantly increase susceptibility to invasive fungal infections. Pathogenic fungi cause billions of infections every year and have an unmet clinical need, with many infections associated with unacceptably high mortality rates that primarily affect vulnerable patients with underlying immune defects. Lipid metabolism has been increasingly appreciated to significantly influence macrophage function, particularly of macrophages residing in lipid-rich organs, such as the brain, or macrophages specialized at clearing dead cells including alveolar macrophages in the lungs. In this review, we provide an overview of macrophage lipid metabolism, and discuss how lipid recycling and dysregulation affect key macrophage functions relevant for antifungal immunity including phagocytosis, functional polarization, and inflammasome activation. We focus on the fungal pathogen Cryptococcus neoformans, as this is the most common cause of death from fungal infection in humans and because several lines of evidence have already linked lipid metabolism in the regulation of C. neoformans and macrophage interactions.
    Keywords:  Cryptococcus neoformans; cholesterol; macrophages; meningitis
    DOI:  https://doi.org/10.1128/mbio.03057-23
  14. Drug Resist Updat. 2024 Aug 31. pii: S1368-7646(24)00105-5. [Epub ahead of print]77 101147
    Mechanism of staphylococcal resistance to clinically relevant antibiotics.
    Daniela Brdová, Tomáš Ruml, Jitka Viktorová.
      Staphylococcus aureus, a notorious pathogen with versatile virulence, poses a significant challenge to current antibiotic treatments due to its ability to develop resistance mechanisms against a variety of clinically relevant antibiotics. In this comprehensive review, we carefully dissect the resistance mechanisms employed by S. aureus against various antibiotics commonly used in clinical settings. The article navigates through intricate molecular pathways, elucidating the mechanisms by which S. aureus evades the therapeutic efficacy of antibiotics, such as β-lactams, vancomycin, daptomycin, linezolid, etc. Each antibiotic is scrutinised for its mechanism of action, impact on bacterial physiology, and the corresponding resistance strategies adopted by S. aureus. By synthesising the knowledge surrounding these resistance mechanisms, this review aims to serve as a comprehensive resource that provides a foundation for the development of innovative therapeutic strategies and alternative treatments for S. aureus infections. Understanding the evolving landscape of antibiotic resistance is imperative for devising effective countermeasures in the battle against this formidable pathogen.
    Keywords:  Antibiotics; Horizontal gene transfer; Resistance mechanisms; Staphylococcal resistance; Staphylococcus aureus
    DOI:  https://doi.org/10.1016/j.drup.2024.101147
  15. Immunohorizons. 2024 Sep 01. 8(9): 606-621
    α-Hemolysin from Staphylococcus aureus Changes the Epigenetic Landscape of Th17 Cells.
    Joanna Pastwińska, Iwona Karwaciak, Kaja Karaś, Anna Sałkowska, Katarzyna Chałaśkiewicz, Dominik Strapagiel, Marta Sobalska-Kwapis, Jarosław Dastych, Marcin Ratajewski.
      The human body harbors a substantial population of bacteria, which may outnumber host cells. Thus, there are multiple interactions between both cell types. Given the common presence of Staphylococcus aureus in the human body and the role of Th17 cells in controlling this pathogen on mucous membranes, we sought to investigate the effect of α-hemolysin, which is produced by this bacterium, on differentiating Th17 cells. RNA sequencing analysis revealed that α-hemolysin influences the expression of signature genes for Th17 cells as well as genes involved in epigenetic regulation. We observed alterations in various histone marks and genome methylation levels via whole-genome bisulfite sequencing. Our findings underscore how bacterial proteins can significantly influence the transcriptome, epigenome, and phenotype of human Th17 cells, highlighting the intricate and complex nature of the interaction between immune cells and the microbiota.
    DOI:  https://doi.org/10.4049/immunohorizons.2400061
  16. J Inflamm Res. 2024 ;17 5855-5869
    Role of Lipopolysaccharides in the Inflammation and Pyroptosis of Alveolar Epithelial Cells in Acute Lung Injury and Acute Respiratory Distress Syndrome.
    Xiao Shen, Linglin He, Wanru Cai.
      Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a spectrum of common critical respiratory conditions characterized by damage and death of alveolar epithelial cells (AECs). Pyroptosis is a form of programmed cell death with inflammatory characteristics, and activation of pyroptosis markers has been observed in AECs of patients with ALI/ARDS. Lipopolysaccharides (LPS) possess strong pro-inflammatory effects and are a crucial pathological factor leading to ALI in patients and animals. In LPS-induced ALI models, AECs undergo pyroptosis. However, physiologically and pathologically relevant concentrations of LPS lead to minor effects on AEC cell viability and minimal induction of cytokine release in vitro and do not induce classical pyroptosis. Nevertheless, LPS can enter the cytoplasm directly and induce non-classical pyroptosis in AECs when assisted by extracellular vesicles from bacteria, HMGB1, and pathogens. In this review, we have explored the effects of LPS on AECs concerning inflammation, cell viability, and pyroptosis, analyzing key factors that influence LPS actions. Notably, we highlight the intricate response of AECs to LPS within the framework of ALI and ARDS, emphasizing the variable induction of pyroptosis. Despite the minimal effects of LPS on AEC viability and cytokine release in vitro, LPS can induce non-classical pyroptosis under specific conditions, presenting potential pathways for therapeutic intervention. Collectively, understanding these mechanisms is crucial for the development of targeted treatments that mitigate the inflammatory responses in ALI/ARDS, thereby enhancing patient outcomes in these severe respiratory conditions.
    Keywords:  alveolar cell death; cytokine activation; inflammatory response; pathological impact; programmed cell death
    DOI:  https://doi.org/10.2147/JIR.S479051
  17. Endocr Rev. 2024 Sep 05. pii: bnae025. [Epub ahead of print]
    Postbiotic impact on host metabolism and immunity provides therapeutic potential in metabolic disease.
    Han Fang, Rodrigo Rodrigues E-Lacerda, Nicole G Barra, Dana Kukje Zada, Nazli Robin, Alina Mehra, Jonathan D Schertzer.
      The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds such as lipopolysaccharides, muropeptides can have opposing effects on endocrine control of host metabolism where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites such as short chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.
    Keywords:  gut microbiota; inflammation; metabolic diseases; metabolism; postbiotics
    DOI:  https://doi.org/10.1210/endrev/bnae025
  18. mSphere. 2024 Sep 04. e0048824
    A quantitative approach to measure and predict microbiome response to antibiotics.
    Vincent Tu, Yue Ren, Ceylan Tanes, Sagori Mukhopadhyay, Scott G Daniel, Hongzhe Li, Kyle Bittinger.
      Although antibiotics induce sizable perturbations in the human microbiome, we lack a systematic and quantitative method to measure and predict the microbiome's response to specific antibiotics. Here, we introduce such a method, which takes the form of a microbiome response index (MiRIx) for each antibiotic. Antibiotic-specific MiRIx values quantify the overall susceptibility of the microbiota to an antibiotic, based on databases of bacterial phenotypes and published data on intrinsic antibiotic susceptibility. We applied our approach to five published microbiome studies that carried out antibiotic interventions with vancomycin, metronidazole, ciprofloxacin, amoxicillin, and doxycycline. We show how MiRIx can be used in conjunction with existing microbiome analytical approaches to gain a deeper understanding of the microbiome response to antibiotics. Finally, we generate antibiotic response predictions for the oral, skin, and gut microbiome in healthy humans. Our approach is implemented as open-source software and is readily applied to microbiome data sets generated by 16S rRNA marker gene sequencing or shotgun metagenomics.IMPORTANCE: Antibiotics are potent influencers of the human microbiome and can be a source for enduring dysbiosis and antibiotic resistance in healthcare. Existing microbiome data analysis methods can quantify perturbations of bacterial communities but cannot evaluate whether the differences are aligned with the expected activity of a specific antibiotic. Here, we present a novel method to quantify and predict antibiotic-specific microbiome changes, implemented in a ready-to-use software package. This has the potential to be a critical tool to broaden our understanding of the relationship between the microbiome and antibiotics.
    Keywords:  antibiotics; bioinformatics; metagenomics; microbiome
    DOI:  https://doi.org/10.1128/msphere.00488-24
  19. Nature. 2024 Sep 03.
    How a bacterial immune system gets taken apart.
      
    Keywords:  Microbiology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-02816-5
  20. Cell Rep. 2024 Aug 28. pii: S2211-1247(24)01033-7. [Epub ahead of print]43(9): 114682
    MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.
    Hui-Ru Chen, Yidan Sun, Gerhard Mittler, Tobias Rumpf, Maria Shvedunova, Rudolf Grosschedl, Asifa Akhtar.
      Signaling-dependent changes in protein phosphorylation are critical to enable coordination of transcription and metabolism during macrophage activation. However, the role of acetylation in signal transduction during macrophage activation remains obscure. Here, we identify the redox signaling regulator peroxiredoxin 1 (PRDX1) as a substrate of the lysine acetyltransferase MOF. MOF acetylates PRDX1 at lysine 197, preventing hyperoxidation and thus maintaining its activity under stress. PRDX1 K197ac responds to inflammatory signals, decreasing rapidly in mouse macrophages stimulated with bacterial lipopolysaccharides (LPSs) but not with interleukin (IL)-4 or IL-10. The LPS-induced decrease of PRDX1 K197ac elevates cellular hydrogen peroxide accumulation and augments ERK1/2, but not p38 or AKT, phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Our work reveals a regulatory role for redox protein acetylation in signal transduction and coordinating metabolic and transcriptional programs during inflammatory macrophage activation.
    Keywords:  CP: Immunology; CP: Molecular biology; ERK1/2; MAPK; glycolytic metabolism; histone H3 serine 28 phosphorylation; lysine acetyltransferase MOF; macrophage activation; peroxiredoxin; protein acetylation; redox signaling; signal transduction
    DOI:  https://doi.org/10.1016/j.celrep.2024.114682
  21. J Immunol. 2024 Sep 04. pii: ji2300411. [Epub ahead of print]
    Potential Contributions of Human Endogenous Retroviruses in Innate Immune Memory.
    Pengcheng Du, Jiarui Li, Mingxi Hua, Liuluan Zhu, Chen Chen, Hui Zeng.
      The phenomenon wherein innate immune cells adopt long-term inflammatory phenotypes following the first stimuli is named trained immunity and can improve host defense against infections. Transcriptional and epigenetic reprogramming are critical mechanisms of trained immunity; however, the regulatory networks are not entirely clear at present. The human endogenous retroviruses (HERVs) provide large amounts of transcriptional regulators in the regulatory pathways. In this study, we analyzed published large omics data to explore the roles of such "dark matter" of the human genome in trained and tolerant macrophages. We collected 80 RNA sequencing data and 62 sequencing data to detect histone modifications and active regulatory regions from nine published studies on trained and tolerant macrophages. By analyzing the characteristics of transcription and epigenetic modification of HERVs, as well as their association with gene expression, we found that 15.3% of HERVs were transcribed nonrandomly from noncoding regions and enriched in specific HERV families and specific chromosomes, such as chromosomes 11, 15, 17, and 19, and they were highly related with the expression of adjacent genes. We found that 295 differentially expressed HERVs are located in 50-kbp flanking regions of 142 differentially expressed genes. We found epigenetic changes of these HERVs and that overlap with predicted enhancers and identified 35 enhancer-like HERVs. The related genes were highly involved in the activation and inflammatory responses, such as the TLR pathway. Other pathways including phosphoinositide signaling and transport of folate and K+ might be also related with trained immunity, which require further study. These results demonstrated that HERVs might play important roles in trained immunity.
    DOI:  https://doi.org/10.4049/jimmunol.2300411
  22. bioRxiv. 2024 Aug 23. pii: 2024.08.22.609198. [Epub ahead of print]
    CD4 + T cells recruit, then engage macrophages in cognate interactions to clear Mycobacterium tuberculosis from the lungs.
    Samuel H Becker, Christine E Ronayne, Tyler D Bold, Marc K Jenkins.
      IFN-γ-producing CD4 + T cells are required for protection against lethal Mycobacterium tuberculosis ( Mtb ) infections. However, the ability of CD4 + T cells to suppress Mtb growth cannot be fully explained by IFN-γ or other known T cell products. In this study, we show that CD4 + T cell-derived IFN-γ promoted the recruitment of monocyte-derived macrophages (MDMs) to the lungs of Mtb -infected mice. Although the recruited MDMs became quickly and preferentially infected with Mtb , CD4 + T cells rapidly disinfected the MDMs. Clearance of Mtb from MDMs was not explained by IFN-γ, but rather by MHCII-mediated cognate interactions with CD4 + T cells. These interactions promoted MDM expression of glycolysis genes essential for Mtb control. Thus, by recruiting MDMs, CD4 + T cells initiate a cycle of bacterial phagocytosis, Mtb antigen presentation and disinfection in an attempt to clear the bacteria from the lungs.
    DOI:  https://doi.org/10.1101/2024.08.22.609198
  23. J Allergy Clin Immunol. 2024 Aug 27. pii: S0091-6749(24)00867-4. [Epub ahead of print]
    Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.
    Sinéad Ryan, Louise Crowe, Sofía N Almeida Cruz, Matthew D Galbraith, Carol O'Brien, Juliet A Hammer, Ronan Bergin, Shauna K Kellett, Gary E Markey, Taylor M Benson, Olga Fagan, Joaquin M Espinosa, Niall Conlon, Claire L Donohoe, Susan McKiernan, Andrew E Hogan, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson.
      BACKGROUND: Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted the absence of hypoxia signaling through HIF-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy.OBJECTIVES: Herein, we sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE.
    METHODS: In RNA-sequencing derived from EoE patient biopsies, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Bioenergetics analysis using Seahorse was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were employed to delineate metabolic dependency mechanisms required for epithelial differentiation.
    RESULTS: Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsies. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells which portray a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacological glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor DMOG resulted in restored expression of epithelial differentiation markers.
    CONCLUSIONS: An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.
    Keywords:  Eosinophilic esophagitis; HIF-1α; differentiation; glycolysis
    DOI:  https://doi.org/10.1016/j.jaci.2024.07.030
  24. Cell Immunol. 2024 Sep 02. pii: S0008-8749(24)00068-6. [Epub ahead of print]403-404 104865
    BCG immunization induced KLRG1+ NK cells show memory-like responses to mycobacterial and HIV antigens.
    Manuja Gunasena, Mario Alles, Thorsten Demberg, Will Mulhern, Namal P M Liyanage.
      Bacille-Calmette-Guérin (BCG) is the only approved vaccine against Mycobacterium tuberculosis (MTB), offering protection not only against tuberculosis (TB) but also non-related infections. 'Trained immunity' of innate immune cells is considered one of the mechanisms of this broad protection derived through BCG. Here, we investigated the effect of BCG on Natural Killer (NK) cells, a key innate immune cell type, and their subsequent responses to mycobacterial and HIV antigens. We found that BCG-induced KLRG1+ NK cells exhibit significantly higher production of IFNγ, compared to KLRG1- cells, indicating their memory-like responses upon exposure to these antigens (p < 0.05). These findings may be important in regions of high burden of HIV and TB where BCG is routinely administered.
    Keywords:  BCG; HIV; Natural killer cells; Trained immunity
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104865
  25. Curr Opin Chem Biol. 2024 Aug 29. pii: S1367-5931(24)00097-8. [Epub ahead of print]82 102521
    Myeloid C-type lectin receptors in host-pathogen interactions and glycan-based targeting.
    Felix Stegmann, Bernd Lepenies.
      Lectin-glycan interactions play a crucial role in the immune system. An important class of lectins in the innate immune system is myeloid C-type lectin receptors (CLRs). Myeloid CLRs act as pattern recognition receptors and are predominantly expressed by myeloid cells, such as macrophages, dendritic cells, and neutrophils. In innate immunity, CLRs contribute to self/non-self discrimination. While the recognition of pathogen-associated molecular patterns (PAMPs) by CLRs may contribute to a protective immune response, CLR engagement can also be exploited by pathogens for immune evasion. Since various CLRs act as endocytic receptors and trigger distinct signaling pathways in myeloid cells, CLR targeting has proven useful for drug/antigen delivery into antigen-presenting cells and the modulation of immune responses. This review covers recent discoveries of pathogen/CLR interactions and novel approaches for CLR targeting within the period of the past two years.
    Keywords:  C-type lectin; Cell targeting; Dendritic cells; Host–pathogen interaction; Immunomodulation; Innate immunity; Macrophages; One Health; Vaccines
    DOI:  https://doi.org/10.1016/j.cbpa.2024.102521
  26. Nutrients. 2024 Aug 21. pii: 2791. [Epub ahead of print]16(16):
    Survival of Probiotic Bacterial Cells in the Upper Gastrointestinal Tract and the Effect of the Surviving Population on the Colonic Microbial Community Activity and Composition.
    Marlies Govaert, Chloë Rotsaert, Chelsea Vannieuwenhuyse, Cindy Duysburgh, Sophie Medlin, Massimo Marzorati, Harry Jarrett.
      Many health-promoting effects have been attributed to the intake of probiotic cells. However, it is important that probiotic cells arrive at the site of their activity in a viable state in order to exert their beneficial effects. Careful selection of the appropriate probiotic formulation is therefore required as mainly the type of probiotic species/strain and the administration strategy may affect survival of the probiotic cells during the upper gastrointestinal (GIT) passage. Therefore, the current study implemented Simulator of the Human Microbial Ecosystem (SHIME®) technology to investigate the efficacy of different commercially available probiotic formulations on the survival and culturability of probiotic bacteria during upper GIT passage. Moreover, Colon-on-a-Plate (CoaP™) technology was applied to assess the effect of the surviving probiotic bacteria on the gut microbial community (activity and composition) of three human donors. Significantly greater survival and culturability rates were reported for the delayed-release capsule formulation (>50%) as compared to the powder, liquid, and standard capsule formulations (<1%) (p < 0.05), indicating that the delayed-release capsule was most efficacious in delivering live bacteria cells. Indeed, administration of the delayed-release capsule probiotic digest resulted in enhanced production of SCFAs and shifted gut microbial community composition towards beneficial bacterial species. These results thus indicate that careful selection of the appropriate probiotic formulation and administration strategy is crucial to deliver probiotic cells in a viable state at the site of their activity (distal ileum and colon).
    Keywords:  administration strategies; delayed-release capsule; gastrointestinal tract; gut microbiota; probiotics; survival
    DOI:  https://doi.org/10.3390/nu16162791
  27. Virulence. 2024 Sep 04. 2399798
    YjbH contributes to staphylococcus aureus skin pathology and immune response through Agr-mediated α-toxin regulation.
    Aubrey K G McReynolds, Emma A Pagella, Miranda J Ridder, Olivia Rippee, Zachary Clark, Michaella J Rekowski, Michele T Pritchard, Jeffrey L Bose.
      Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-haemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative haemolysis assays we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.
    Keywords:  MRSA; SSTI; Staphylococcus; YjbH; alpha-toxin; necrosis; regulation; s. aureus; skin; virulence factor
    DOI:  https://doi.org/10.1080/21505594.2024.2399798
  28. Methods Mol Biol. 2024 ;2851 151-172
    Lactic Acid Bacteria in the Human Oral Cavity: Assessing Metabolic Functions Relevant to Oral Health and Disease.
    Jumpei Washio, Yuki Abiko, Takuichi Sato, Nobuhiro Takahashi.
      Many perceive lactic acid bacteria as beneficial for health. They are recognized for preventing abnormal fermentation and spoilage of ingested foods by producing lactic acid, which aids in gut acidification. Moreover, lactic acid bacteria are extensively employed in food science. In contrast, lactic acid bacteria in the oral cavity are often perceived as pathogenic factors contributing to the development of dental caries. As a consequence, substantial research has been conducted in oral and dental sciences to explore lactic acid bacteria and the oral microbiome. This research primarily involves analyzing bacterial flora, investigating metabolic activities such as acid production, and investigating metabolic regulation within the oral environment. The oral cavity serves as the gateway to the digestive tract and respiratory system, characterized by a constantly fluctuating environment that significantly impacts the metabolic activity of lactic acid bacteria. Hence, when investigating oral lactic acid bacteria, it is crucial to adopt research plans and methodologies that account for these metabolic environment changes. In this section, we present some of the methods employed in our study.
    Keywords:  Acid production; Actinomyces; Dental caries; Metabolism; Streptococcus
    DOI:  https://doi.org/10.1007/978-1-0716-4096-8_14
  29. Inflamm Res. 2024 Sep 05.
    Probiotic nucleotides increase IL-10 expression in airway macrophages to mitigate airway allergy.
    Jinmei Xue, Zhizhen Liu, Bailing Xie, Rui Dong, Juan Wu, Yisha Wu, Zhihan Xu, Yuhe Tian, Yao Wei, Zhigang Geng, Lei Lu, Yu Liu, Jun Xie, Pingchang Yang.
      BACKGROUND: Dysfunctional immune regulation plays a crucial role in the pathogenesis of airway allergies. Macrophages are one of the components of the immune regulation cells. The aim of this study is to elucidate the role of lysine demethylase 5 A (KDM5A) in maintaining macrophages' immune regulatory ability.METHODS: DNA was extracted from Lactobacillus rhamnosus GG to be designated as LgDNA. LgDNA was administered to the mice through nasal instillations. M2 macrophages (M2 cells) were isolated from the airway tissues using flow cytometry.
    RESULTS: We found that airway M2 cells of mice with airway Th2 polarization had reduced amounts of IL-10 and KDM5A. Mice with Kdm5a deficiency in M2 cells showed the airway Th2 polarization. The expression of Kdm5a in airway M2 cells was enhanced by nasal instillations containing LgDNA. KDM5A mediated the effects of LgDNA on inducing the Il10 expression in airway M2 cells. Administration of LgDNA mitigated experimental airway allergy.
    CONCLUSIONS: M2 macrophages in the airway tissues of mice with airway allergy show low levels of KDM5A. By upregulating KDM5A expression, LgDNA can increase Il10 expression and reconcile airway Th2 polarization.
    Keywords:  IL-10; Immune regulation; Macrophage; Probiotics; Th2
    DOI:  https://doi.org/10.1007/s00011-024-01940-2
  30. Cell Signal. 2024 Aug 30. pii: S0898-6568(24)00338-3. [Epub ahead of print]123 111370
    Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion.
    Fan Ao-Di, Lin Han-Qing, Wang Xi-Zheng, Yang Ke, Guo Hong-Xin, Zhang Hai-Xia, Fan Guan-Wei, Li-Lan.
      Acute myocardial infarction (AMI) is the leading cause of death worldwide, and reperfusion therapy is a critical therapeutic approach to reduce myocardial ischemic injury and minimize infarct size. However, ischemia/reperfusion (I/R) itself also causes myocardial injury, and inflammation is an essential mechanism by which it leads to myocardial injury, with macrophages as crucial immune cells in this process. Macrophages are innate immune cells that maintain tissue homeostasis, host defence during pathogen infection, and repair during tissue injury. During the acute phase of I/R, M1-type macrophages generate a pro-inflammatory milieu, clear necrotic myocardial tissue, and further recruit mononuclear (CCR2+) macrophages. Over time, the reparative (M2 type) macrophages gradually became dominant. In recent years, metabolic studies have shown a clear correlation between the metabolic profile of macrophages and their phenotype and function. M1-type macrophages are mainly characterized by glycolytic energy supply, and their tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS) processes are impaired. In contrast, M2 macrophages rely primarily on OXPHOS for energy. Changing the metabolic profile of macrophages can alter the macrophage phenotype. Altered energy pathways are also present in macrophages during I/R, and intervention in this process contributes to earlier and greater M2 macrophage infiltration, which may be a potential target for the treatment of myocardial I/R injury. Therefore, this paper mainly reviews the characteristics of macrophage energy metabolism alteration and phenotypic transition during I/R and its mechanism of mediating myocardial injury to provide a basis for further research in this field.
    Keywords:  Macrophage; Metabolic reprogramming; Myocardial ischemia-reperfusion
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111370
  31. Curr Pharm Biotechnol. 2024 Sep 05.
    Pathophysiological and Clinical Potential of Human Microbiome: Microbe-based Therapeutic Insights.
    Somali Sanyal, Kumud Nigam, Sukriti Singh, Puja Lohani, Manish Dwivedi.
      The human microbiota represents the community and diverse population of microbes within the human body, which comprises approximately 100 trillion micro-organisms. They exist in the human gastrointestinal tract and various other organs and are now considered virtual body organs. It is mainly represented by bacteria but also includes viruses, fungi, and protozoa. Although there is a heritable component to the gut microbiota, environmental factors related to diet, drugs, and anthropometry determine the composition of the microbiota. Besides the gastrointestinal tract, the human body also harbours microbial communities in the skin, oral and nasal cavities, and reproductive tract. The current review demonstrates the role of gut microbiota and its involvement in processing food, drugs, and immune responses. The discussion focuses on the implications of human microbiota in developing several diseases, such as gastrointestinal infections, metabolic disorders, malignancies, etc., through symbiotic relationships. The microbial population may vary depending on the pathophysiological condition of an individual and thus may be exploited as a therapeutic and clinical player. Further, we need a more thorough investigation to establish the correlation between microbes and pathophysiology in humans and propose them as potential therapeutic targets.
    Keywords:  Microbiota; food; gut intestinal microbiota; oral microbiota; reproductive microbiota; skin microbiota
    DOI:  https://doi.org/10.2174/0113892010314433240823113111
  32. MedComm (2020). 2024 Sep;5(9): e693
    Cell death pathways: molecular mechanisms and therapeutic targets for cancer.
    Shaohui Wang, Sa Guo, Jing Guo, Qinyun Du, Cen Wu, Yeke Wu, Yi Zhang.
      Cell death regulation is essential for tissue homeostasis and its dysregulation often underlies cancer development. Understanding the different pathways of cell death can provide novel therapeutic strategies for battling cancer. This review explores several key cell death mechanisms of apoptosis, necroptosis, autophagic cell death, ferroptosis, and pyroptosis. The research gap addressed involves a thorough analysis of how these cell death pathways can be precisely targeted for cancer therapy, considering tumor heterogeneity and adaptation. It delves into genetic and epigenetic factors and signaling cascades like the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways, which are critical for the regulation of cell death. Additionally, the interaction of the microenvironment with tumor cells, and particularly the influence of hypoxia, nutrient deprivation, and immune cellular interactions, are explored. Emphasizing therapeutic strategies, this review highlights emerging modulators and inducers such as B cell lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), chloroquine, and innovative approaches to induce ferroptosis and pyroptosis. This review provides insights into cancer therapy's future direction, focusing on multifaceted approaches to influence cell death pathways and circumvent drug resistance. This examination of evolving strategies underlines the considerable clinical potential and the continuous necessity for in-depth exploration within this scientific domain.
    Keywords:  apoptosis; autophagy; cancer therapy; cell death; drug resistance; ferroptosis; necroptosis; pyroptosis; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.693
  33. Toxicol Mech Methods. 2024 Sep 02. 1-28
    Silica-induced ROS in alveolar macrophages and its role on the formation of pulmonary fibrosis via polarizing macrophages into M2 phenotype: A review.
    Shu-Ling Du, Yu-Ting Zhou, Hui-Jie Hu, Li Lin, Zhao-Qiang Zhang.
      Alveolar Macrophages (AMs), the first line against the invasion of foreign invaders, play a predominant role in the pathogenesis of silicosis. Studies have shown that inhaled silica dust is recognized and engulfed by AMs, resulting in the production of large amounts of silica-induced ROS, including particle-derived Reactive Oxygen Species (ROS) and macrophage-derived ROS. These ROS change the microenvironment of the AMs where the macrophage phenotype is stimulated to swift from M0 to M1 and/or M2, and ultimately emerge as the M2 phenotype to trigger silicosis. This is a complex process accompanied by various molecular biological events. Unfortunately, the detailed processes and mechanisms have not been systematically described. In this review, we first systematically introduce the process of ROS induced by silica in AMs. Then describe the role and molecular mechanism of M2-type macrophage polarization caused by silica-induced ROS. Finally, we review the mechanism of pulmonary fibrosis induced by M2 polarized AMs. We conclude that silica-induced ROS initiate the fibrotic process of silicosis by inducing macrophage into M2 phenotype, and that targeted intervention of silica-induced ROS in AMs can reprogram the macrophage polarization and ameliorate the pathogenesis of silicosis.
    Keywords:  Alveolar macrophages; M2 polarized macrophages; Pulmonary fibrosis; Silicosis; silica-induced ROS
    DOI:  https://doi.org/10.1080/15376516.2024.2400323
  34. Adv Neurobiol. 2024 ;37 607-622
    Metabolic Control of Microglia.
    Monica Emili Garcia-Segura, Stefano Pluchino, Luca Peruzzotti-Jametti.
      Microglia, immune sentinels of the central nervous system (CNS), play a critical role in maintaining its health and integrity. This chapter delves into the concept of immunometabolism, exploring how microglial metabolism shapes their diverse immune functions. It examines the impact of cell metabolism on microglia during various CNS states, including homeostasis, development, aging, and inflammation. Particularly in CNS inflammation, the chapter discusses how metabolic rewiring in microglia can initiate, resolve, or perpetuate inflammatory responses. The potential of targeting microglial metabolism as a therapeutic strategy for chronic CNS disorders with prominent innate immune cell activation is also explored.
    Keywords:  Immunometabolism; Lipid metabolism; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_34
  35. Mediterr J Rheumatol. 2024 Jun;35(2): 220-233
    Current Approaches to Prevent or Reverse Microbiome Dysbiosis in Chronic Inflammatory Rheumatic Diseases.
    Jan René Nkeck, Ange Larissa Tchuisseu-Kwangoua, Adeline Pelda, Wilson Chia Tamko, Saquinatou Hamadjoda, Doris Bibi Essama, Baudelaire Fojo, Moustapha Niasse, Saïdou Diallo, Madeleine Ngandeu-Singwé.
      Advances in knowledge of the microbiome and its relationship with the immune system have led to a better understanding of the pathogenesis of chronic inflammatory rheumatic diseases (CIRD). Indeed, the microbiome dysbiosis now occupies a particular place with implications for the determinism and clinical expression of CIRD, as well as the therapeutic response of affected patients. Several approaches exist to limit the impact of the microbiome during CIRD. This review aimed to present current strategies to prevent or reverse microbiome dysbiosis based on existing knowledge, in order to provide practical information to healthcare professionals treating patients suffering from CIRD.
    Keywords:  chronic inflammatory rheumatic diseases; dysbiosis; microbiome; prevention; sub-Saharan Africa; treatment
    DOI:  https://doi.org/10.31138/mjr.240224.cap
  36. bioRxiv. 2024 Jul 24. pii: 2024.07.23.604740. [Epub ahead of print]
    scRNA-seq identifies unique macrophage population in murine model of ozone induced asthma exacerbation.
    Jess L Ray, Joshua Walum, Daria Jelic, Ryelie Barnes, Ian D Bentley, Rodney D Britt, Joshua A Englert, Megan N Ballinger.
      Ozone (O 3 ) inhalation triggers asthmatic airway hyperresponsiveness (AHR), but the mechanisms by which this occurs are unknown. Previously, we developed a murine model of dust mite, ragweed, and aspergillus (DRA)-induced allergic lung inflammation followed by O 3 exposure for mechanistic investigation. The present study used single cell RNA-sequencing for unbiased profiling of immune cells within the lungs of mice exposed to DRA, O 3 , or DRA+O 3 , to identify the components of the immune cell niche that contribute to AHR. Alveolar macrophages (AMs) had the greatest number of differentially expressed genes following DRA+O 3 , most of which were unique to the 2-hit exposure. Following DRA+O 3 , AMs activated transcriptional pathways related to cholesterol biosynthesis, degradation of the extracellular matrix, endosomal TLR processing, and various cytokine signals. We also identified AM and monocyte subset populations that were unique to the DRA+O 3 group. These unique AMs activated gene pathways related to inflammation, sphingolipid metabolism, and bronchial constriction. The unique monocyte population had a gene signature that suggested phospholipase activation and increased degradation of the extracellular matrix. Flow cytometry analysis of BAL immune cells showed recruited monocyte-derived AMs after DRA and DRA+O 3 , but not after O 3 exposure alone. O 3 alone increased BAL neutrophils but this response was attenuated in DRA+O 3 mice. DRA-induced changes in the airspace immune cell profile were reflected in elevated BAL cytokine/chemokine levels following DRA+O 3 compared to O 3 alone. The present work highlights the role of monocytes and AMs in the response to O 3 and suggests that the presence of distinct subpopulations following allergic inflammation may contribute to O 3 -induced AHR.
    DOI:  https://doi.org/10.1101/2024.07.23.604740
  37. Toxicol Appl Pharmacol. 2024 Sep 02. pii: S0041-008X(24)00281-3. [Epub ahead of print] 117083
    VEGFR1 TK signaling protects the lungs against LPS-induced injury by suppressing the activity of alveolar macrophages and enhancing the anti-inflammatory function of monocyte-derived macrophages.
    Mayuko Osada, Atsushi Yamashita, Seishiro Akinaga, Kanako Hosono, Yoshiya Ito, Masabumi Shibuya, Yasushi Asari, Hideki Amano.
      Acute lung injury (ALI) is characterized by hyperinflammation followed by vascular leakage and respiratory failure. Vascular endothelial growth factor (VEGF)-A is critical for capillary permeability; however, the role of VEGF receptor 1 (VEGFR1) signaling in ALI progression remains unclear. Here, we show that deletion of VEGFR1 tyrosine kinase (TK) signaling in mice exacerbates lipopolysaccharide (LPS)-induced ALI as evidenced by excessive pro-inflammatory cytokine production and interleukin(IL)-1β-producing neutrophil recruitment to inflamed lung tissues. ALI development involves reduced alveolar macrophage (AM) levels and recruitment of monocyte-derived macrophages (MDMs) in a VEGFR1 TK-dependent manner. VEGFR1 TK signaling reduced pro-inflammatory cytokine levels in cultured AMs. VEGFR1 TK-expressing MDMs displayed an anti-inflammatory macrophage phenotype. Additionally, the transplantation of VEGFR1 TK-expressing bone marrow (BM)-derived macrophages into VEGFR1 TK-deficient mice reduced lung inflammation. Treatment with placental growth factor (PlGF), an agonist for VEGFR1, protected the lung against LPS-induced ALI associated with increased MDMs. These results suggest that VEGFR1 TK signaling prevents LPS-induced ALI by suppressing the pro-inflammatory activity of AMs and enhancing the anti-inflammatory function of MDMs.
    Keywords:  ARDS; Lung Injury; Macrophages; VEGFR1
    DOI:  https://doi.org/10.1016/j.taap.2024.117083
  38. Front Cell Infect Microbiol. 2024 ;14 1443719
    Phosphatidylserine liposomes induce a phagosome acidification-dependent and ROS-mediated intracellular killing of Mycobacterium abscessus in human macrophages.
    Tommaso Olimpieri, Noemi Poerio, Greta Ponsecchi, Gustavo Di Lallo, Marco Maria D'Andrea, Maurizio Fraziano.
      Mycobacterium abscessus (Mab) is an opportunistic nontuberculous mycobacterium responsible of difficult-to-treat pulmonary infections in vulnerable patients, such as those suffering from Cystic Fibrosis (CF), where it represents a major cause of morbidity and mortality. Additionally, due to the intrinsic extensive antimicrobial resistance spectrum displayed by this species and the side effects reported for some available antibiotics, the therapeutic management of such infections remains extremely difficult. In the present study, we show that phosphatidylserine liposomes (PS-L) enhance intracellular mycobacterial killing of Mab infected human macrophages with functional or pharmacologically inhibited cystic fibrosis conductance regulator (CFTR), by a mechanism involving phagosome acidification and reactive oxygen species (ROS) production. Additionally, PS-L significantly reduce proinflammatory response of Mab infected macrophages in terms of NF-kB activation and TNF-α production, irrespective of CFTR inhibition. Altogether, these results represent the proof of concept for a possible future development of PS-L as a therapeutic strategy against difficult-to-treat Mab infection.
    Keywords:  Mycobacterium abscessus; cystic fibrosis; host-directed therapy; innate immunity; liposome; phosphatidylserine
    DOI:  https://doi.org/10.3389/fcimb.2024.1443719
  39. Int Immunopharmacol. 2024 Aug 31. pii: S1567-5769(24)01540-6. [Epub ahead of print]142(Pt A): 113019
    Reprogramming macrophage metabolism following myocardial infarction: A neglected piece of a therapeutic opportunity.
    Baoping Xie, Jiahua Li, Yanmei Lou, Qi Chen, Ying Yang, Rong Zhang, Zhongqiu Liu, Liu He, Yuanyuan Cheng.
      Given the global prevalence of myocardial infarction (MI) as the leading cause of mortality, there is an urgent need to devise novel strategies that target reducing infarct size, accelerating cardiac tissue repair, and preventing detrimental left ventricular (LV) remodeling. Macrophages, as a predominant type of innate immune cells, undergo metabolic reprogramming following MI, resulting in alterations in function and phenotype that significantly impact the progression of MI size and LV remodeling. This article aimed to delineate the characteristics of macrophage metabolites during reprogramming in MI and elucidate their targets and functions in cardioprotection. Furthermore, we summarize the currently proposed regulatory mechanisms of macrophage metabolic reprogramming and identify the regulators derived from endogenous products and natural small molecules. Finally, we discussed the challenges of macrophage metabolic reprogramming in the treatment of MI, with the goal of inspiring further fundamental and clinical research into reprogramming macrophage metabolism and validating its potential therapeutic targets for MI.
    Keywords:  Endogenous metabolites; Macrophage; Metabolism reprogramming; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.intimp.2024.113019
  40. Asia Pac Allergy. 2024 Aug;14(3): 97-102
    Enhanced IL-37-IL-1R8 axis is negatively associated with inflammatory and clinical severity of chronic rhinosinusitis with nasal polyps.
    Jia Zhang, Yujie Cao, Kun Chen, Xianting Hu, Chun Zhou, Lei Li, Miaomiao Han, Dehui Wang, Huabin Li.
      Background: The importance of IL-37 and downstream signal in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) demanding further investigation.Objective: We sought to address the potential importance of the IL-37-IL-1R8 axis in regulating inflammatory response in patients with CRSwNP.
    Methods: Nasal polyp (NP) tissues and control sinonasal tissues were obtained from adult CRSwNP, chronic rhinosinusitis without nasal polyps patients and healthy control subjects. The mRNA and protein levels of IL-37 and IL-1R8 in nasal tissues were examined by using quantitative PCR, immunohistochemical staining, and immunoblotting. In addition, the regulation of IL-1R8 expression was evaluated in human nasal epithelial cells (HNECs) in the presence of different stimuli.
    Results: The mRNA and protein levels of IL-37 and IL-1R8 were significantly elevated in nasal polyps compared with that in control tissues. IL-37 and IL-1R8 were mainly distributed in the epithelial layer and lamina propria of tissues. IL-1R8 mRNA level in nasal polys was negatively associated with eosinophil and neutrophil infiltration, as well as endoscopic score and computed tomography score. Moreover, the mRNA expression of IL-1R8 in HNECs was significantly increased by toll-like receptor agonists, but significantly inhibited by proinflammatory cytokines, which can be rescued by using steroid (DEX).
    Conclusion: Our findings showed that enhanced IL-37-IL-1R8 axis in NP tissues was negatively associated with inflammatory and clinical severity of CRSwNP patients, which could be considered as a future therapeutic target in CRSwNP patients.
    Keywords:  Chronic rhinosinusitis; IL-1 family; IL-1R8; IL-37; nasal polyps
    DOI:  https://doi.org/10.5415/apallergy.0000000000000148
  41. Biochim Biophys Acta Mol Basis Dis. 2024 Aug 29. pii: S0925-4439(24)00476-9. [Epub ahead of print]1870(8): 167482
    Regulation of host metabolism and defense strategies to survive neonatal infection.
    Ziyuan Wu, Nguyen Tran Nam Tien, Ole Bæk, Jingren Zhong, Björn Klabunde, Tinh Thu Nguyen, Nguyen Thi Hai Yen, Nguyen Phuoc Long, Duc Ninh Nguyen.
      Two distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection.
    Keywords:  Defense strategies; Disease resistance; Disease tolerance; Glycolysis; Mitochondrial activity; Neonatal infection
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167482
  42. bioRxiv. 2024 Aug 04. pii: 2024.08.03.606494. [Epub ahead of print]
    Weight loss-induced adipose macrophage memory improves local Staphylococcus aureus clearance in male mice.
    McArthur Bolden, Xenia D Davis, Edward R Sherwood, Julia K Bohannon, Heather L Caslin.
      Different stimuli can induce innate immune memory to improve pathogen defense or worsen cardiometabolic disease. However, it is less clear if the same stimuli can induce both the protective and detrimental effects of innate immune memory. We previously showed that weight loss induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. In this study, we investigated the effect of weight loss on macrophage cytokine production and overall survival in a mouse model of infection. Male C57Bl/6J mice were put on high-fat or low-fat diets over 18 weeks to induce weight gain or weight loss. Lean mice served as controls. All mice were then infected IV with 2.5×10^6 CFU Staphylococcus aureus . Tissues were collected from 10 mice/group at day 3 and the remaining animals were followed for survival. Weight gain mice had the highest blood neutrophils and the highest bacterial burden in the kidney. However, there was no significant difference in survival. The weight loss group had the highest plasma TNF-α and a significant reduction in bacterial burden in the adipose tissue that correlated with increased adipose macrophage cytokine production. Thus, weight loss-induced adipose macrophage memory may both improve local S.aureus clearance and worsen diabetes risk upon weight regain. Collectively, these findings support the notion that innate immune memory is an evolutionarily protective mechanism that also contributes to the development of cardiometabolic diseases.
    DOI:  https://doi.org/10.1101/2024.08.03.606494
  43. mBio. 2024 Sep 06. e0081024
    Bystander monocytic cells drive infection-independent NLRP3 inflammasome response to SARS-CoV-2.
    Leon L Hsieh, Monika Looney, Alexis Figueroa, Guido Massaccesi, Georgia Stavrakis, Eduardo U Anaya, Franco R D'Alessio, Alvaro A Ordonez, Andrew S Pekosz, Victor R DeFilippis, Petros C Karakousis, Andrew H Karaba, Andrea L Cox.
      The pathogenesis of COVID-19 is associated with a hyperinflammatory immune response. Monocytes and macrophages play a central role in this hyperinflammatory response to SARS-CoV-2. NLRP3 inflammasome activation has been observed in monocytes of patients with COVID-19, but the mechanism and consequences of inflammasome activation require further investigation. In this study, we inoculated a macrophage-like THP-1 cell line, primary differentiated human nasal epithelial cell (hNEC) cultures, and primary monocytes with SARS-CoV-2. We found that the activation of the NLRP3 inflammasome in macrophages does not rely on viral replication, receptor-mediated entry, or actin-dependent entry. SARS-CoV-2 productively infected hNEC cultures without triggering the production of inflammasome cytokines IL-18 and IL-1β. Importantly, these cytokines did not inhibit viral replication in hNEC cultures. SARS-CoV-2 inoculation of primary monocytes led to inflammasome activation and induced a macrophage phenotype in these cells. Monocytic cells from bronchoalveolar lavage (BAL) fluid, but not from peripheral blood, of patients with COVID-19, showed evidence of inflammasome activation, expressed the proinflammatory marker CD11b, and displayed oxidative burst. These findings highlight the central role of activated macrophages, as a result of direct viral sensing, in COVID-19 and support the inhibition of IL-1β and IL-18 as potential therapeutic strategies to reduce immunopathology without increasing viral replication.IMPORTANCE: Inflammasome activation is associated with severe COVID-19. The impact of inflammasome activation on viral replication and mechanistic details of this activation are not clarified. This study advances our understanding of the role of inflammasome activation in macrophages by identifying TLR2, NLRP3, ASC, and caspase-1 as dependent factors in this activation. Further, it highlights that SARS-CoV-2 inflammasome activation is not a feature of nasal epithelial cells but rather activation of bystander macrophages in the airway. Finally, we demonstrate that two pro inflammatory cytokines produced by inflammasome activation, IL-18 and IL-1β, do not restrict viral replication and are potential targets to ameliorate pathological inflammation in severe COVID-19.
    Keywords:  NLRP3; SARS-CoV-2; cytokines; inflammasome; macrophages
    DOI:  https://doi.org/10.1128/mbio.00810-24
  44. Curr Microbiol. 2024 Sep 06. 81(10): 346
    Immunomodulation in Non-traditional Therapies for Methicillin-resistant Staphylococcus aureus (MRSA) Management.
    Suthi Subbarayudu, S Karthick Raja Namasivayam, Jesu Arockiaraj.
      The rise of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge in clinical settings due to its ability to evade conventional antibiotic treatments. This overview explores the potential of immunomodulatory strategies as alternative therapeutic approaches to combat MRSA infections. Traditional antibiotics are becoming less effective, necessitating innovative solutions that harness the body's immune system to enhance pathogen clearance. Recent advancements in immunotherapy, including the use of antimicrobial peptides, phage therapy, and mechanisms of immune cells, demonstrate promise in enhancing the body's ability to clear MRSA infections. However, the exact interactions between these therapies and immunomodulation are not fully understood, underscoring the need for further research. Hence, this review aims to provide a broad overview of the current understanding of non-traditional therapeutics and their impact on immune responses, which could lead to more effective MRSA treatment strategies. Additionally, combining immunomodulatory agents with existing antibiotics may improve outcomes, particularly for immunocompromised patients or those with chronic infections. As the landscape of antibiotic resistance evolves, the development of effective immunotherapeutic strategies could play a vital role in managing MRSA infections and reducing reliance on traditional antibiotics. Future research must focus on optimizing these approaches and validating their efficacy in diverse clinical populations to address the urgent need for effective MRSA management strategies.
    DOI:  https://doi.org/10.1007/s00284-024-03875-7
  45. Immun Inflamm Dis. 2024 Sep;12(9): e70012
    Mycobacterium tuberculosis protein Rv2652c enhances intracellular survival by inhibiting host immune responses.
    Jihong Li, Yafeng Dou.
      BACKGROUNDS: Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis, secretes a multitude of proteins that modulate the host's immune response to ensure its own persistence. The region of difference (RD) genes encoding proteins play key roles in TB immunity and pathogenesis. Nevertheless, the roles of the majority of RD-encoded proteins remain to be elucidated.OBJECTS: To elucidate the role of Rv2652c located in RD13 in Mtb on bacterial growth, bacterial survival, and host immune response.
    METHODS: We constructed the strain MS_Rv2652c which over-expresses Mtb RD-encoding protein Rv2652c in M. smegmatis (MS), and compared it with the wild strain in the bacterial growth, bacterial survival, virulence of Rv2652c, and determined the effect of MS_Rv2652c on host immune response in macrophages.
    RESULTS: Rv2652c protein is located at cell wall of MS_Rv2652c strain and also an integral component of the Mtb H37Rv cell wall. Rv2652c can enhance the resistance of recombinant MS to various stressors. Moreover, Rv2652c inhibits host proinflammatory responses via modulation of the NF-κB pathway, thereby promoting Mtb survival in vitro and in vivo.
    CONCLUSION: Our data suggest that cell wall protein Rv2652c plays an important role in creating a favorable environment for bacterial survival by modulating host signals and could be established as a potential TB drug target.
    Keywords:  Mycobacterium tuberculosis; Rv2652c; host immune responses; intracellular survival
    DOI:  https://doi.org/10.1002/iid3.70012
  46. Front Microbiol. 2024 ;15 1431785
    Oral microbiota and metabolites: key players in oral health and disorder, and microbiota-based therapies.
    Narjess Bostanghadiri, Mobina Kouhzad, Elahe Taki, Zahra Elahi, Amin Khoshbayan, Tahereh Navidifar, Davood Darban-Sarokhalil.
      The review aimed to investigate the diversity of oral microbiota and its influencing factors, as well as the association of oral microbiota with oral health and the possible effects of dysbiosis and oral disorder. The oral cavity harbors a substantial microbial burden, which is particularly notable compared to other organs within the human body. In usual situations, the microbiota exists in a state of equilibrium; however, when this balance is disturbed, a multitude of complications arise. Dental caries, a prevalent issue in the oral cavity, is primarily caused by the colonization and activity of bacteria, particularly streptococci. Furthermore, this environment also houses other pathogenic bacteria that are associated with the onset of gingival, periapical, and periodontal diseases, as well as oral cancer. Various strategies have been employed to prevent, control, and treat these disorders. Recently, techniques utilizing microbiota, like probiotics, microbiota transplantation, and the replacement of oral pathogens, have caught the eye. This extensive examination seeks to offer a general view of the oral microbiota and their metabolites concerning oral health and disease, and also the resilience of the microbiota, and the techniques used for the prevention, control, and treatment of disorders in this specific area.
    Keywords:  bacteria; microbiota metabolites; oral cavity; oral microbiota; periodontal disease
    DOI:  https://doi.org/10.3389/fmicb.2024.1431785
  47. Oncotarget. 2024 Sep 04. 15 609-613
    Trained and ready - the case for an inflammatory memory for hematopoietic stem and progenitor cells in the AML niche.
    Ding-Wen Chen, Eric K Wafula, Peter Kurre.
      Lifelong hematopoiesis is sustained by crosstalk between hematopoietic stem and progenitor cells (HSPCs) and specialized bone marrow niches. Acute myeloid leukemia (AML) upends that balance, as leukemic blasts secrete factors that remodel the bone marrow into a self-reinforcing leukemic niche. The inflammatory secretome behind this compartmental adaptation accounts for a progressive decline in hematopoietic function that leads to diagnosis and persists through early treatment. Not surprisingly, the mediators of an acute inflammatory injury and HSPC suppression have attracted much attention in an effort to alleviate morbidity and improve outcomes. HSPCs typically recover during disease remission and re-expand in the bone marrow (BM), but little is known about potentially lasting consequences for stem cells and progenitors. We recently showed that AML-experienced HSPCs actively participate in the inflammatory process during leukemic progression. HSPCs are constituent components of the innate immune system, and elegant studies of infection and experimental inflammation over the past decade have described the generation of an adoptively transferable, innate immune memory. Building on this paradigm, we discuss the potential translational relevance of a durable legacy in AML-experienced HSPC.
    Keywords:  acute myeloid leukemia; hematopoietic stem and progenitor cells; inflammation; innate immune reprogramming; trained immunity
    DOI:  https://doi.org/10.18632/oncotarget.28642
  48. Nature. 2024 Sep 02.
    An ethical way forward for Indigenous microbiome research.
    Sam Jones.
      
    Keywords:  Developing world; Ethics; Microbiome
    DOI:  https://doi.org/10.1038/d41586-024-02792-w
  49. Front Immunol. 2024 ;15 1357444
    Innate immunity in peripheral tissues is differentially impaired under normal and endotoxic conditions in aging.
    Ji Yeon Noh, Hye Won Han, Da Mi Kim, Erin D Giles, Yuhua Z Farnell, Gus A Wright, Yuxiang Sun.
      Chronic low-grade inflammation is a hallmark of aging, aka "inflammaging", which is linked to a wide range of age-associated diseases. Immune dysfunction increases disease susceptibility, and increases morbidity and mortality of aging. Innate immune cells, including monocytes, macrophages and neutrophils, are the first responders of host defense and the key mediators of various metabolic and inflammatory insults. Currently, the understanding of innate immune programming in aging is largely fragmented. Here we investigated the phenotypic and functional properties of innate immune cells in various peripheral tissues of young and aged mice under normal and endotoxic conditions. Under the steady state, aged mice showed elevated pro-inflammatory monocytes/macrophages in peripheral blood, adipose tissue, liver, and colon. Under lipopolysaccharide (LPS)-induced inflammatory state, the innate immune cells of aged mice showed a different response to LPS stimulus than that of young mice. LPS-induced immune responses displayed differential profiles in different tissues and cell types. In the peripheral blood, when responding to LPS, the aged mice showed higher neutrophils, but lower pro-inflammatory monocytes than that in young mice. In the peritoneal fluid, while young mice exhibited significantly elevated pro-inflammatory neutrophils and macrophages in response to LPS, aged mice exhibited decreased pro-inflammatory neutrophils and variable cytokine responses in macrophages. In the adipose tissue, LPS induced less infiltrated neutrophils but more infiltrated macrophages in old mice than young mice. In the liver, aged mice showed a more robust increase of pro-inflammatory macrophages compared to that in young mice under LPS stimulation. In colon, macrophages showed relatively mild response to LPS in both young and old mice. We have further tested bone-marrow derived macrophages (BMDM) from young and aged mice, we found that BMDM from aged mice have impaired polarization, displaying higher expression of pro-inflammatory markers than those from young mice. These data collectively suggest that innate immunity in peripheral tissues is impaired in aging, and the dysregulation of immunity is tissue- and cell-dependent. Our findings in the rodent model underscore the complexity of aging immunity. Further investigation is needed to determine whether the immune profile observed in aged mice is applicable in age-associated diseases in humans.
    Keywords:  aging; immunometabolism; inflammaging; innate immunity; macrophages; monocytes; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2024.1357444
  50. bioRxiv. 2024 Aug 15. pii: 2024.08.14.607930. [Epub ahead of print]
    Dysregulated Airway Host Defense in Hyper IgE Syndrome due to STAT3 Mutations.
    Ling Sun, Samantha A Walls, Hong Dang, Nancy L Quinney, Patrick R Sears, Taraneh Sadritabrizi, Koichi Hasegawa, Kenichi Okuda, Takanori Asakura, Xiuya Chang, Meiqi Zheng, Yu Mikami, Felicia U Dizmond, Daniela Danilova, Lynn Zhou, Anshulika Deshmukh, Deborah M Cholon, Giorgia Radicioni, Troy D Rogers, William J Kissner, Matthew R Markovetz, Tara N Guhr Lee, Mark I Gutay, Charles R Esther, Michael Chua, Barbara R Grubb, Camille Ehre, Mehmet Kesimer, David B Hill, Lawrence E Ostrowski, Brian Button, Martina Gentzsch, Chevalia Robinson, Kenneth N Olivier, Alexandra F Freeman, Scott H Randell, Wanda K O'Neal, Richard C Boucher, Gang Chen.
      Rationale: Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES syndrome is characterized by chronic pulmonary infection and inflammation, suggesting impairment of pulmonary innate host defense.Objectives: To identify airway epithelial host defense defects consequent to STAT3 mutations that, in addition to reported mutant STAT3 immunologic abnormalities, produce pulmonary infection.
    Methods: STAT3-HIES sputum was evaluated for biochemical/biophysical properties. STAT3-HIES excised lungs were harvested for histology; bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific mutation (R382W), expressed by lentiviruses, and a STAT3 knockout, generated by CRISPR/Cas9, were maintained in normal human bronchial epithelia under basal or inflammatory (IL1β) conditions. Effects of STAT3 deficiency on transcriptomics, and epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed.
    Measurements and Main Results: Mucus concentrations and viscoelasticity were increased in STAT3-HIES sputum. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 deficiency impaired CFTR-dependent fluid and mucin secretion, inhibited expression of antimicrobial peptides, cytokines, and chemokines, and acidified airway surface liquid at baseline and post-IL1β exposure in vitro. Notably, mutant STAT3 suppressed IL1R1 expression. STAT3 mutations also inhibited ciliogenesis in vivo and impaired mucociliary transport in vitro, a process mediated via HES6 suppression. Administration of a γ-secretase inhibitor increased HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells.
    Conclusions: STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with STAT3-HIES immune deficiency, contributes to chronic pulmonary infection.
    DOI:  https://doi.org/10.1101/2024.08.14.607930
  51. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2395099
    The hidden base of the iceberg: gut peptidoglycome dynamics is foundational to its influence on the host.
    Richard Wheeler, Ivo Gomperts Boneca.
      The intestinal microbiota of humans includes a highly diverse range of bacterial species. All these bacteria possess a cell wall, composed primarily of the macromolecule peptidoglycan. As such, the gut also harbors an abundant and varied peptidoglycome. A remarkable range of host physiological pathways are regulated by peptidoglycan fragments that originate from the gut microbiota and enter the host system. Interactions between the host system and peptidoglycan can influence physiological development and homeostasis, promote health, or contribute to inflammatory disease. Underlying these effects is the interplay between microbiota composition and enzymatic processes that shape the intestinal peptidoglycome, dictating the types of peptidoglycan generated, that subsequently cross the gut barrier. In this review, we highlight and discuss the hidden and emerging functional aspects of the microbiome, i.e. the hidden base of the iceberg, that modulate the composition of gut peptidoglycan, and how these fundamental processes are drivers of physiological outcomes for the host.
    Keywords:  Gut; Microbiota; PG trafficking; chronic inflammation; host signaling; peptidoglycan; peptidoglycan processing; prophage
    DOI:  https://doi.org/10.1080/19490976.2024.2395099
  52. Mol Biotechnol. 2024 Sep 06.
    Quercetin Alleviates the Progression of Chronic Rhinosinusitis Without Nasal Polyps by Inhibiting Nasal Mucosal Inflammation and Epithelial Apoptosis.
    Lingzhao Meng, Xiaopeng Qu, Pengyu Tao, Jiajia Dong, Rui Guo.
      Chronic rhinosinusitis (CRS) is a common chronic inflammatory upper respiratory tract, has a major subtype of CRS without nasal polyps (CRSsNP), constituting a great global health problem. Quercetin exerts the important roles in several inflammatory diseases. However, its function in CRSsNP remains unclear. In this study, quercetin dose-dependently alleviated allergic nasal symptoms of increased frequencies of sneezing and nasal scratching in Staphylococcus aureus-constructed CRSsNP mice. Importantly, quercetin attenuated the histopathological changes of nasal mucosa tissue in model mice, including mucosal thickening, glandular hyperplasia, noticeable mast cells, and inflammatory cell infiltration. Concomitantly, quercetin alleviated the increased mucosal inflammation in CRSsNP mice by suppressing the transcripts and releases of pro-inflammatory IL-1β, IL-6, and IL-4. Notably, quercetin restrained X-box binding protein 1 (XBP1)-mediated activation of the HIF-1α/wnt-β-catenin axis in nasal mucosal tissues in CRSsNP model. Intriguingly, intranasal instillation of Lv-XBP1 offset the protective efficacy of quercetin against the progression of CRSsNP by suppressing the production of inflammatory cytokine IL-1β, IL-6, and IL-4, frequency of sneezing and nasal scratching, and histopathological changes of nasal mucosa tissues. In vitro, higher expression of XBP1 was observed in human nasal epithelial cells (HNECs) of CRSsNP relative to the normal HNECs. Moreover, elevation of XBP1 by Lv-XBP1 treatment suppressed cell proliferation and increased apoptosis of CRSsNP HNECs. Mechanistically, XBP1 overexpression increased the expression of HIF-1α and β-catenin, indicating the activation of the HIF-1α/wnt-β-catenin axis. Nevertheless, treatment with quercetin inhibited XBP1-induced cell apoptosis and reversed XBP1-mediated inhibition in cell proliferation in HNECs, as well as the activation of the HIF-1α/wnt-β-catenin axis. Thus, these findings reveal that quercetin may attenuate the progression of CRSsNP by inhibiting nasal mucosal inflammation and epithelial barrier dysfunction via blocking the XBP1/HIF-1α/wnt-β-catenin pathway, supporting a promising agent against CRSsNP.
    Keywords:  CRSsNP; Epithelial barrier dysfunction; Inflammation; Quercetin; XBP1
    DOI:  https://doi.org/10.1007/s12033-024-01269-5
  53. Curr Opin Immunol. 2024 Sep 02. pii: S0952-7915(24)00047-5. [Epub ahead of print]90 102457
    Friendly fire: recognition of self by the innate immune system.
    Veit Hornung, Moritz M Gaidt.
      The innate immune system employs two different strategies to detect pathogens: first, it recognizes microbial components as ligands of pattern recognition receptors (pattern-triggered immunity [PTI]), and second, it detects the activities of pathogen-encoded effectors (effector-triggered immunity [ETI]). Recently, these pathogen-centric concepts were expanded to include sensing of self-derived signals during cellular distress or damage (damage-triggered immunity [DTI]). This extension relied on broadening the PTI model to include damage-associated molecular patterns (DAMPs). However, applying the pattern recognition framework of PTI to DTI overlooks the critical role of sterile activation of ETI pathways. We argue that both PTI and ETI pathways are prone to erroneous detection of self, which is largely attributable to 'friendly fire' rather than protective immune activation. This erroneous activation is inherent to the trade-off between sensitivity and specificity of immune sensing and might be tolerated because its detrimental effects emerge late in life, a phenomenon known as antagonistic pleiotropy.
    DOI:  https://doi.org/10.1016/j.coi.2024.102457
  54. Microbiol Mol Biol Rev. 2024 Sep 04. e0017122
    Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.
    Harshini Weerasinghe, Helen Stölting, Adam J Rose, Ana Traven.
      SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes.
    Keywords:  Aspergillus; Candida; Cryptococcus; disease tolerance; fungal infection; fungal pathogens; immunity; immunometabolism; metabolic disease; metabolism
    DOI:  https://doi.org/10.1128/mmbr.00171-22
  55. Nature. 2024 Aug 29.
    Are you what you eat? Biggest-ever catalogue of food microbes finds out.
    Ewen Callaway.
      
    Keywords:  DNA sequencing; Microbiology; Microbiome
    DOI:  https://doi.org/10.1038/d41586-024-02778-8
  56. Pathogens. 2024 Aug 02. pii: 654. [Epub ahead of print]13(8):
    Systemic Factors Effecting Human Beta-Defensins in Oral Cavity.
    Nur Atalay, Nur Balci, Mervi Gürsoy, Ulvi Kahraman Gürsoy.
      Human beta-defensins are host defense peptides with broad antimicrobial and inflammatory functions. In the oral cavity, these peptides are produced mainly by the keratinocytes of the epithelium; however, fibroblasts, monocytes, and macrophages also contribute to oral human beta-defensin expressions. The resident and immune cells of the oral cavity come into contact with various microbe-associated molecular patterns continuously and simultaneously. The overall antimicrobial cellular response is highly influenced by local and environmental factors. Recent studies have produced evidence showing that not only systemic chronic diseases but also systemic factors like hyperglycemia, pregnancy, the long-term use of certain vitamins, and aging can modulate oral cellular antimicrobial responses against microbial challenges. Therefore, the aim of this narrative review is to discuss the role of systemic factors on oral human beta-defensin expressions.
    Keywords:  aging; defensins; hyperglycemia; periodontal diseases; periodontium; pregnancy; retinoids; vitamin D
    DOI:  https://doi.org/10.3390/pathogens13080654
  57. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Aug;40(8): 743-747
    [Progress on iron metabolism and ferroptosis in macrophages].
    Linchao Ba, Wei Li, Zhengjun Fan, Pengfei Ma.
      Macrophages play vital roles in iron metabolism and are also modulated by iron. Macrophages are crucial to the recycling of iron and systemic iron homeostasis, and the functional heterogeneity of macrophages contributes to the different effects on iron metabolism. Conversely, iron can affect the development, function, and polarization of macrophages. Macrophages can initiate ferroptosis through a series of signaling pathways when overloaded with intracellular iron. Macrophages ferroptosis can aggravate local inflammatory reactions and promote the progression of various diseases such as metabolism, infection, and inflammation, so inhibiting macrophages ferroptosis may be an important therapeutic target. In addition, inhibiting M1-like macrophages ferroptosis and promoting M2-like macrophages ferroptosis are important in inhibiting the progression of malignant tumors.
  58. Eur Respir J. 2024 Sep 04. pii: 2301983. [Epub ahead of print]
    Microenvironmental acidification by pneumococcal sugar consumption fosters barrier disruption and immune suppression in the human alveolus.
    Diana Fatykhova, Verena N Fritsch, Keerthana Siebert, Karen Methling, Michael Lalk, Tobias Busche, Jörn Kalinowski, January Weiner, Dieter Beule, Wilhelm Bertrams, Thomas P Kohler, Sven Hammerschmidt, Anna Löwa, Mara Fischer, Maren Mieth, Katharina Hellwig, Doris Frey, Jens Neudecker, Jens C Rueckert, Mario Toennies, Torsten T Bauer, Mareike Graff, Hong-Linh Tran, Stephan Eggeling, Achim D Gruber, Haike Antelmann, Stefan Hippenstiel, Andreas C Hocke.
      Streptococcus pneumoniae (S.p.) is the most common causative agent of community-acquired pneumonia worldwide. A key pathogenic mechanism that exacerbates severity of disease is the disruption of the alveolar-capillary barrier. However, the specific virulence mechanisms responsible for this in the human lung are not yet fully understood.In this study, we infected living human lung tissue with S.p. and observed a significant degradation of the central junctional proteins occludin and VE-cadherin, indicating barrier disruption. Surprisingly, neither pneumolysin, bacterial hydrogen peroxide nor pro-inflammatory activation were sufficient to cause this junctional degradation. Instead, pneumococcal infection led to a significant decrease of pH (approximately 6), resulting in acidification of the alveolar microenvironment, which was linked to junctional degradation. Stabilising the pH at physiological levels during infection reversed this effect, even in a therapeutic-like approach.Further analysis of bacterial metabolites and RNA sequencing revealed sugar consumption and subsequent lactate production were the major factors contributing to bacterially induced alveolar acidification, which also hindered the release of critical immune factors.Our findings highlight bacterial metabolite-induced acidification as an independent virulence mechanism for barrier disruption and inflammatory dysregulation in pneumonia. Thus, our data suggest that strictly monitoring and buffering alveolar pH during infections caused by fermentative bacteria could serve as an adjunctive therapeutic strategy for sustaining barrier integrity and immune response.
    DOI:  https://doi.org/10.1183/13993003.01983-2023
  59. Adv Neurobiol. 2024 ;37 263-286
    Roles in Innate Immunity.
    Kaira A Church, Astrid E Cardona, Sarah C Hopp.
      Microglia are best known as the resident phagocytes of the central nervous system (CNS). As a resident brain immune cell population, microglia play key roles during the initiation, propagation, and resolution of inflammation. The discovery of resident adaptive immune cells in the CNS has unveiled a relationship between microglia and adaptive immune cells for CNS immune-surveillance during health and disease. The interaction of microglia with elements of the peripheral immune system and other CNS resident cells mediates a fine balance between neuroprotection and tissue damage. In this chapter, we highlight the innate immune properties of microglia, with a focus on how pattern recognition receptors, inflammatory signaling cascades, phagocytosis, and the interaction between microglia and adaptive immune cells regulate events that initiate an inflammatory or neuroprotective response within the CNS that modulates immune-mediated disease exacerbation or resolution.
    Keywords:  Antigen presentation; BBB; Immune-surveillance; Inflammasome; Microglia; Microglia sensome; Phagocytosis; Vasculature
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_15
  60. bioRxiv. 2024 Jul 31. pii: 2023.09.06.556606. [Epub ahead of print]
    Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.
    Preeti Yadav, Javier Gómez Ortega, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper Wang, Tatsuya Tsukui, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L Eckalbar, Ari B Molofsky, Paul J Wolters, Stanley J Tamaki, Trever Bivona, Adam R Abate, Allon Wagner, Kevin M Tharp, Mallar Bhattacharya.
      Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.
    DOI:  https://doi.org/10.1101/2023.09.06.556606
  61. Infect Immun. 2024 Sep 03. e0025124
    Heterogeneity of Salmonella enterica lipopolysaccharide counteracts macrophage and antimicrobial peptide defenses.
    Linda M Heffernan, Anna-Lisa E Lawrence, Haley A Marcotte, Amit Sharma, Aria X Jenkins, Damilola Iguwe, Jennifer Rood, Scott W Herke, Mary X O'Riordan, Basel H Abuaita.
      Salmonella enterica is comprised of over 2,500 serovars, in which non-typhoidal serovars (NTS), Enteritidis (SE), and Typhimurium (STM) are the most clinically associated with human infections. Although NTS have similar genetic elements to cause disease, phenotypic variation including differences in lipopolysaccharide (LPS) composition may control immune evasion. Here, we demonstrate that macrophage host defenses and LL-37 antimicrobial efficacy against SE and STM are substantially altered by LPS heterogeneity. We found that SE evades macrophage killing by inhibiting phagocytosis while STM survives better intracellularly post-phagocytosis. SE-infected macrophages failed to activate the inflammasomes and subsequently produced less interleukin-1β (IL-1β), IL-18, and interferon λ. Inactivation of LPS biosynthesis genes altered LPS composition, and the SE LPS-altered mutants could no longer inhibit phagocytosis, inflammasome activation, and type II interferon signaling. In addition, SE and STM showed differential susceptibility to the antimicrobials LL-37 and colistin, and alteration of LPS structure substantially increased susceptibility to these molecules. Collectively, our findings highlight that modification of LPS composition by Salmonella increases resistance to host defenses and antibiotics.
    Keywords:  LL-37; Salmonella; colistin; inflammasomes; interferons; lipopolysaccharide; macrophages; phagocytosis
    DOI:  https://doi.org/10.1128/iai.00251-24
  62. Eur J Immunol. 2024 Sep 04. e2350943
    Colony stimulating factor 1 receptor (Csf1r) expressing cell ablation in mafia (macrophage-specific Fas-induced apoptosis) mice alters monocyte landscape and atherosclerotic lesion characteristics.
    Indira Medina, Elias B Wieland, Lieve Temmerman, Jeroen J T Otten, Beatriz Bermudez, Ilze Bot, Timo Rademakers, Erwin Wijnands, Leon Schurgers, Barend Mees, Theo J C van Berkel, Pieter Goossens, Erik A L Biessen.
      Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion might provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis. To deplete monocytes/macrophages we used atherosclerosis-susceptible Apoe- /- mice, bearing a MaFIA (macrophage-Fas-induced-apoptosis) suicide construct under control of the Csf1r (CD115) promotor, where selective apoptosis of Csf1r-expressing cells was induced in a controlled manner, by administration of a drug, AP20187. Systemic induction of apoptosis resulted in a decrease in lesion macrophages and smooth-muscle cells. Plaque size and necrotic core size remained unaffected. Two weeks after the systemic depletion of macrophages, we observed a replenishment of the myeloid compartment. Myelopoiesis was modulated resulting in an expansion of CSF1Rlo myeloid cells in the circulation and a shift from Ly6chi monocytes toward Ly6cint and Ly6clo populations in the spleen. Local apoptosis induction led to a decrease in plaque burden and macrophage content with marginal effects on the circulating myeloid cells. Local, but not systemic depletion of Csf1r+ myeloid cells resulted in decreased plaque burden. Systemic depletion led to CSF1Rlo-monocyte expansion in blood, possibly explaining the lack of effects on plaque development.
    Keywords:  Apoptosis; Atherogenesis; Atherosclerosis; Cardiovascular immunology; Cardiovascular inflammation; Colony stimulating factor 1; Csf1r; Inflammation; Innate immunity; MaFIA; Macrophages; Macrophage‐specific Fas‐induced apoptosis; Monocyte infiltration; Monocytes; Myeloid cell depletion
    DOI:  https://doi.org/10.1002/eji.202350943
  63. Eur Respir Rev. 2024 Jul;pii: 230259. [Epub ahead of print]33(173):
    Fine particulate matter manipulates immune response to exacerbate microbial pathogenesis in the respiratory tract.
    Jason Ma, Ya-Fang Chiu, Chih-Chen Kao, Chun-Ning Chuang, Chi-Yuan Chen, Chih-Ho Lai, Ming-Ling Kuo.
      Particulate matter with a diameter ≤2.5 μm (PM2.5) poses a substantial global challenge, with a growing recognition of pathogens contributing to diseases associated with exposure to PM2.5 Recent studies have focused on PM2.5, which impairs the immune cells in response to microbial infections and potentially contributes to the development of severe diseases in the respiratory tract. Accordingly, changes in the respiratory immune function and microecology mediated by PM2.5 are important factors that enhance the risk of microbial pathogenesis. These factors have garnered significant interest. In this review, we summarise recent studies on the potential mechanisms involved in PM2.5-mediated immune system disruption and exacerbation of microbial pathogenesis in the respiratory tract. We also discuss crucial areas for future research to address the gaps in our understanding and develop effective strategies to combat the adverse health effects of PM2.5.
    DOI:  https://doi.org/10.1183/16000617.0259-2023
This page is being maintained by Thomas Krichel. It was last updated on 2024‒09‒11 at 5:16.