bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒03‒17
53 papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Alendronate modulates cytokine responses in healthy young individuals after BCG vaccination.
  2. Trained innate immunity modulates osteoblast and osteoclast differentiation.
  3. Innate Immune Training in Chickens for Improved Defense against Pathogens: A Review.
  4. Understanding the Dynamics of Human Defensin Antimicrobial Peptides: Pathogen Resistance and Commensal Induction.
  5. Control of immune cell signaling by the immuno-metabolite itaconate.
  6. Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.
  7. Gut microbe guides alveolar macrophages to fight flu.
  8. Metabolic regulation of type I interferon production.
  9. Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases.
  10. Human Macrophages Activate Bystander Neutrophils' Metabolism and Effector Functions When Challenged with Mycobacterium tuberculosis.
  11. Bacterial antigens and asthma: a comparative study of common respiratory pathogenic bacteria.
  12. Mitochondria: the gatekeepers between metabolism and immunity.
  13. Metabolic reprogramming of the inflammatory response in the nervous system: the crossover between inflammation and metabolism.
  14. Monitoring Staphylococcus aureus nasal colonization murine model using a bioluminescent methicillin-resistant S. aureus (MRSA).
  15. Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis.
  16. Neutralizing Staphylococcus aureus PAMPs that Trigger Cytokine Release from THP-1 Monocytes.
  17. Editorial: Innovative approaches to immune tolerance and regulation with gene, cellular, protein, and microbiome based therapeutics.
  18. The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.
  19. Molecular Aspects of the Functioning of Pathogenic Bacteria Biofilm Based on Quorum Sensing (QS) Signal-Response System and Innovative Non-Antibiotic Strategies for Their Elimination.
  20. TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.
  21. Invade to evade: E. coli's gutsy survival strategies.
  22. Chronic obstructive pulmonary disease and the airway microbiome: A review for clinicians.
  23. Pyruvate Kinase M2 Nuclear Translocation Regulate Ferroptosis-Associated Acute Lung Injury in Cytokine Storm.
  24. How do sphingosine-1-phosphate affect immune cells to resolve inflammation?
  25. Eosinophils are the dominant type2 marker for the current indication of biological treatment in severe uncontrolled chronic rhinosinusitis with nasal polyps.
  26. The Longitudinal Microbial and Metabolic Landscape of infant Cystic Fibrosis: The gut-lung axis.
  27. Quantitative proteomics reveals tissue-specific, infection-induced and species-specific neutrophil protein signatures.
  28. Strategies of Helicobacter pylori in evading host innate and adaptive immunity: insights and prospects for therapeutic targeting.
  29. Editorial: Antibiotics overuse as the driving force behind antimicrobial resistance.
  30. Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity.
  31. Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases.
  32. Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis.
  33. A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane-bound and soluble BDCA-2.
  34. The positioning of ceftobiprole in the treatment of Staphylococcus aureus bacteremia.
  35. Delayed neutrophil shedding of CD62L in patients with chronic rhinosinusitis with nasal polyps and asthma: Implications for Staphylococcus aureus colonization and corticosteroid treatment.
  36. The role of macrophage polarization and cellular crosstalk in the pulmonary fibrotic microenvironment: a review.
  37. IFNγ insufficiency during mouse intra-vaginal Chlamydia trachomatis infection exacerbates alternative activation in macrophages with compromised CD40 functions.
  38. Microbiome and its impact on fetal and neonatal brain development: current opinion in pediatrics.
  39. Krüppel-like Factor (KLF) family members control expression of genes required for serous cavity and alveolar macrophage identities.
  40. VEGFR-3 signaling in macrophages: friend or foe in disease?
  41. Abnormal functional lymphoid tolerance and enhanced myeloid exocytosis are characteristics of resting and stimulated PBMCs in cystic fibrosis patients.
  42. A new piece of the microbiota pie: Mining 'omics for DNA inversion states.
  43. Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases.
  44. Inflammasomes in epithelial innate immunity: front line warriors.
  45. Pneumococcal sialidase promotes bacterial survival by fine-tuning of pneumolysin-mediated membrane disruption.
  46. Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release.
  47. Control of the Development, Distribution, and Function of Innate-Like Lymphocytes and Innate Lymphoid Cells by the Tissue Microenvironment.
  48. Efficacy and safety of a synbiotic infant formula for the prevention of respiratory and gastrointestinal infections: A randomized controlled trial.
  49. Innate immune cells: Key players of orchestra in modulating tumor microenvironment (TME).
  50. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis.
  51. Implications of blood type in personalised microbiome therapy.
  52. The epidermal lipid-microbiome loop and immunity: Important players in atopic dermatitis.
  53. Antibiotic administration aggravates asthma by disrupting gut microbiota and the intestinal mucosal barrier in an asthma mouse model.
  1. Immunol Lett. 2024 Mar 11. pii: S0165-2478(24)00025-7. [Epub ahead of print]267 106851
    Alendronate modulates cytokine responses in healthy young individuals after BCG vaccination.
    Ozlem Bulut, Gizem Kilic, Priya A Debisarun, Rutger Jan Röring, Sarah Sun, Manon Kolkman, Esther van Rijssen, Jaap Ten Oever, Hans Koenen, Luis Barreiro, Jorge Domínguez-Andrés, Mihai G Netea.
      Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by epigenetic and metabolic reprogramming. Cholesterol synthesis plays an amplifying role in trained immunity through mevalonate release. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, can inhibit cholesterol synthesis. We explored their effects on trained immunity induced by BCG in a placebo-controlled clinical study (NL74082.091.20) in young, healthy individuals. Participants receiving single-dose oral alendronate on the day of BCG vaccination had more neutrophils and plasma cells one month after treatment. Alendronate led to reduced proinflammatory cytokine production by PBMCs stimulated with heterologous bacterial and viral stimuli one month later. Furthermore, the addition of alendronate transcriptionally suppressed multiple immune response pathways in PBMCs upon stimulation. Our findings indicate that N-BPs modulate the long-lasting effects of BCG vaccination on the cytokine production capacity of innate immune cells.
    Keywords:  Alendronate; BCG; Bisphosphonates; Trained immunity
    DOI:  https://doi.org/10.1016/j.imlet.2024.106851
  2. Stem Cell Rev Rep. 2024 Mar 13.
    Trained innate immunity modulates osteoblast and osteoclast differentiation.
    N R Rahmani, R Belluomo, M C Kruyt, D Gawlitta, L A B Joosten, H Weinans, M Croes.
      Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages' memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette-Guérin (BCG) to induce a 'trained' state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a 'tolerance' state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine.
    Keywords:  Bone regeneration; Innate immune memory; MSC; Macrophage; Osteoimmunology
    DOI:  https://doi.org/10.1007/s12015-024-10711-9
  3. J Poult Sci. 2024 ;61 2024008
    Innate Immune Training in Chickens for Improved Defense against Pathogens: A Review.
    Yukinori Yoshimura, Takahiro Nii, Naoki Isobe.
      The avian immune system plays a vital role in poultry production to obtain good productibility and products that are safe and of high quality. Historically, adaptive immunity has been the main target of vaccination. However, over the past decade, innate immunity has been reported to be enhanced in different animals through vaccination and feed additives. This enhancement is due to innate immune memory termed "trained immunity," in which epigenetic and metabolic reprogramming play significant roles. Although reports on trained immunity in poultry are limited, several studies have suggested that vaccinations and feed additives affect the innate immunity. This review discusses the possible effects of vaccination and β-glucan on innate immunity for potential incorporation in advanced strategies to enhance the defense function in poultry while considering the information on trained immunity in mammals.
    Keywords:  innate immunity; reprograming; trained immunity; vaccines; β-glucan
    DOI:  https://doi.org/10.2141/jpsa.2024008
  4. Appl Biochem Biotechnol. 2024 Mar 13.
    Understanding the Dynamics of Human Defensin Antimicrobial Peptides: Pathogen Resistance and Commensal Induction.
    Veenayohini Kumaresan, Yoganathan Kamaraj, Satheeshkumar Subramaniyan, Ganesh Punamalai.
      Antimicrobial peptides (AMPs), also known as host defense peptides, are petite molecules with inherent microbicidal properties that are synthesized by the host's innate immune response. These peptides serve as an initial barrier against pathogenic microorganisms, effectively eliminating them. Human defensin (HD) AMPs represent a prominent group of peptides involved in the innate immune response of humans. These peptides are primarily produced by neutrophils and epithelial cells, serving as a crucial defense mechanism against invading pathogens. The extensive research conducted has focused on the broad spectrum of antimicrobial activities and multifaceted immunomodulatory functions exhibited by human defensin AMPs. During the process of co-evolution between hosts and bacterial pathogens, bacteria have developed the ability to recognize and develop an adaptive response to AMPs to counterattack their bactericidal activity by different antibiotic-resistant mechanisms. However, numerous non-pathogenic commensal bacteria elicit the upregulation of defensins as a means to surmount the resistance mechanisms implemented by pathogens. The precise mechanism underlying the induction of HD by commensal organisms remains to be fully understood. This review summarizes the most recent research on the expression of human defensin by pathogens and discusses the various defense mechanisms used by pathogens to counter host AMP production. We also mention recent developments in the commensal induction of defensin AMPs. A better knowledge of the pathogens' defensin AMP resistance mechanisms and commensals' induction of AMP expression may shed light on the creation of fresh antibacterial tactics to get rid of bacterial infection.
    Keywords:  Antimicrobial peptides; Antimicrobial resistance; Commensal bacteria; Human defensins; Immune system
    DOI:  https://doi.org/10.1007/s12010-024-04893-8
  5. Front Immunol. 2024 ;15 1352165
    Control of immune cell signaling by the immuno-metabolite itaconate.
    Roland Lang, Md Nur A Alam Siddique.
      Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.
    Keywords:  ACOD1; IRG1; itaconate; macrophages; metabolism; post-translational modification; signal transduction; transport
    DOI:  https://doi.org/10.3389/fimmu.2024.1352165
  6. Cell Host Microbe. 2024 Mar 08. pii: S1931-3128(24)00056-8. [Epub ahead of print]
    Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.
    Xin Zhou, Xiaotao Shen, Jethro S Johnson, Daniel J Spakowicz, Melissa Agnello, Wenyu Zhou, Monica Avina, Alexander Honkala, Faye Chleilat, Shirley Jingyi Chen, Kexin Cha, Shana Leopold, Chenchen Zhu, Lei Chen, Lin Lyu, Daniel Hornburg, Si Wu, Xinyue Zhang, Chao Jiang, Liuyiqi Jiang, Lihua Jiang, Ruiqi Jian, Andrew W Brooks, Meng Wang, Kévin Contrepois, Peng Gao, Sophia Miryam Schüssler-Fiorenza Rose, Thi Dong Binh Tran, Hoan Nguyen, Alessandra Celli, Bo-Young Hong, Eddy J Bautista, Yair Dorsett, Paula B Kavathas, Yanjiao Zhou, Erica Sodergren, George M Weinstock, Michael P Snyder.
      To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.
    Keywords:  insulin resistance; longitudinal profiling; microbiome host interaction; microbiome stability; nasal microbiome; oral microbiome; precision medicine; prediabetes; skin microbiome; stool microbiome
    DOI:  https://doi.org/10.1016/j.chom.2024.02.012
  7. Cell Host Microbe. 2024 Mar 13. pii: S1931-3128(24)00050-7. [Epub ahead of print]32(3): 296-298
    Gut microbe guides alveolar macrophages to fight flu.
    Tao Wang, Yanling Wang, Yushi Yao.
      The intestinal microbiota is associated with defense against respiratory viral infections. In this issue of Cell Host & Microbe, Ngo and colleagues1 show that intestinal commensal segmented filamentous bacteria reprogram alveolar macrophages with improved influenza-viral-neutralizing and phagocytic functions while maintaining inflammatory anergy to better protect the lung.
    DOI:  https://doi.org/10.1016/j.chom.2024.02.007
  8. Immunol Rev. 2024 Mar 11.
    Metabolic regulation of type I interferon production.
    Shane M O'Carroll, Fiona D R Henkel, Luke A J O'Neill.
      Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.
    Keywords:  Immunometabolism; interferons; macrophage; metabolism
    DOI:  https://doi.org/10.1111/imr.13318
  9. FEBS J. 2024 Mar 12.
    Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases.
    Laura M Merlo Pich, Athanasios Ziogas, Mihai G Netea.
      Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non-genetic factors playing an important role. During the last decade, long-term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re-infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases.
    Keywords:  autoinflammation; cytokines; inflammasome; interferons; trained immunity
    DOI:  https://doi.org/10.1111/febs.17116
  10. Int J Mol Sci. 2024 Mar 01. pii: 2898. [Epub ahead of print]25(5):
    Human Macrophages Activate Bystander Neutrophils' Metabolism and Effector Functions When Challenged with Mycobacterium tuberculosis.
    Dearbhla M Murphy, Anastasija Walsh, Laura Stein, Andreea Petrasca, Donal J Cox, Kevin Brown, Emily Duffin, Gráinne Jameson, Sarah A Connolly, Fiona O'Connell, Jacintha O'Sullivan, Sharee A Basdeo, Joseph Keane, James J Phelan.
      Neutrophils are dynamic cells, playing a critical role in pathogen clearance; however, neutrophil infiltration into the tissue can act as a double-edged sword. They are one of the primary sources of excessive inflammation during infection, which has been observed in many infectious diseases including pneumonia and active tuberculosis (TB). Neutrophil function is influenced by interactions with other immune cells within the inflammatory lung milieu; however, how these interactions affect neutrophil function is unclear. Our study examined the macrophage-neutrophil axis by assessing the effects of conditioned medium (MΦ-CM) from primary human monocyte-derived macrophages (hMDMs) stimulated with LPS or a whole bacterium (Mycobacterium tuberculosis) on neutrophil function. Stimulated hMDM-derived MΦ-CM boosts neutrophil activation, heightening oxidative and glycolytic metabolism, but diminishes migratory potential. These neutrophils exhibit increased ROS production, elevated NET formation, and heightened CXCL8, IL-13, and IL-6 compared to untreated or unstimulated hMDM-treated neutrophils. Collectively, these data show that MΦ-CM from stimulated hMDMs activates neutrophils, bolsters their energetic profile, increase effector and inflammatory functions, and sequester them at sites of infection by decreasing their migratory capacity. These data may aid in the design of novel immunotherapies for severe pneumonia, active tuberculosis and other diseases driven by pathological inflammation mediated by the macrophage-neutrophil axis.
    Keywords:  Mycobacterium tuberculosis; glycolysis; granulocytes; immunometabolism; infection; neutrophil function; neutrophil metabolism; neutrophil priming and activation; polymorphonuclear cells; tuberculosis
    DOI:  https://doi.org/10.3390/ijms25052898
  11. J Asthma. 2024 Mar 13. 1-15
    Bacterial antigens and asthma: a comparative study of common respiratory pathogenic bacteria.
    Jie Pang, Yifan Shi, Dan Peng, Lele Cui, Yingjie Xu, Wenjing Wang, Yue Hu, Yiran Yang, Jingjing Wang, Xiaofeng Qin, Yue Zhang, Hao Meng, Dan Wang, Ge Bai, Huihui Yuan, Jie Liu, Zhe Lv, Yan Li, Ye Cui, Wenjun Wang, Kewu Huang, Chris J Corrigan, Wei Wang, Yan Chen, Sun Ying.
      In a previous study we have shown that, in the presence of interleukin (IL)-33, repeated, per-nasal challenge of murine airways with Streptococcus pneumoniae (S. pneumoniae) organisms induces human asthma-like airways inflammation. It is not clear, however, whether this effect is unique or manifest in response to other common respiratory pathogens. To explore this, airways of BALB/c mice were repeatedly challenged per-nasally with formaldehyde-inactivated bacterial bodies in the presence or absence of murine recombinant IL-33. Serum concentrations of S.pneumoniae, Moraxella catarrhalis (M.catarrhalis) and Haemophilus influenzae (H.influenzae) lysates-specific IgE were measured in patients with asthma and control subjects. We showed that in the presence of IL-33, repeated, per-nasal airways exposure to the bodies of these bacteria induced airways hyperresponsiveness (AHR) in the experimental mice. This was accompanied by cellular infiltration into bronchoalveolar lavage fluid (BALF), eosinophilic infiltration and mucous hypertrophy of the lung tissue, with elevated local expression of some type 2 cytokines and elevated, specific IgG and IgE in the serum. The precise characteristics of the inflammation evoked by exposure to each bacterial species were distinguishable. These results suggest that in the certain circumstances, inhaled or commensal bacterial body antigens of both Gram-positive (S. pneumoniae) and Gram-negative (M. catarrhalis and H. influenzae) respiratory tract bacteria may initiate type 2 inflammation typical of asthma in the airways. In addition, we demonstrated that human asthmatic patients manifest elevated serum concentrations of M.catarrhalis- and H.influenzae-specific IgE.
    Keywords:  Haemophilus influenzae antigen; IL-33; Moraxella catarrhalis antigen; Streptococcus pneumoniae antigen; asthma
    DOI:  https://doi.org/10.1080/02770903.2024.2330063
  12. Front Immunol. 2024 ;15 1334006
    Mitochondria: the gatekeepers between metabolism and immunity.
    Giovanna Trinchese, Fabiano Cimmino, Angela Catapano, Gina Cavaliere, Maria Pina Mollica.
      Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions.
    Keywords:  immunometabolism; metabolic flexibility; metabolic reprogramming; mitochondrial dynamics; mitochondrial function
    DOI:  https://doi.org/10.3389/fimmu.2024.1334006
  13. Neural Regen Res. 2024 Oct 01. 19(10): 2189-2201
    Metabolic reprogramming of the inflammatory response in the nervous system: the crossover between inflammation and metabolism.
    Jesus Amo-Aparicio, Charles A Dinarello, Ruben Lopez-Vales.
      Metabolism is a fundamental process by which biochemicals are broken down to produce energy (catabolism) or used to build macromolecules (anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.
    DOI:  https://doi.org/10.4103/1673-5374.391330
  14. Lab Anim. 2024 Mar 09. 236772231209790
    Monitoring Staphylococcus aureus nasal colonization murine model using a bioluminescent methicillin-resistant S. aureus (MRSA).
    Juliana G da Silva, Juliana Pc Boechat, Bruno Dj Silva, Rodrigo Müller, José Pm Senna.
      Staphylococcus aureus nasal carriage is considered a risk factor for infections, and the development of nasal decolonization strategies is highly relevant. Despite they are not naturally colonized by Staphylococcus, mice are a good model for S. aureus nasal colonization. Murine models are easy to manipulate, and inter-laboratory reproducibility makes them suitable for nasal colonization studies. Strategies using bioluminescent bacteria allow for the monitoring of infection over time without the need to sacrifice animals for bacterial quantification. In this study, we evaluated S. aureus nasal colonization in three mouse strains (BALB/c, C57BL/6, and Swiss Webster) using a bioluminescent strain (SAP231). In vitro, a visible Bioluminescent Signal Emission (BLSE) was observed until 106 bacteria and detected by IVIS® imaging system up to 104 cells. Animals were inoculated with one or two doses of approximately 109 colony-forming units (CFU) of SAP231. Swiss Webster mice showed the longest colonization time, with some animals presenting BLSE for up to 140 h. In addition, BLSE was higher in this strain. BALB/c and C57BL/6 strains showed consistent BLSE results for 48 h. BLSE intensity was higher in Swiss Webster inoculated with both doses. Three different positions for image capture were evaluated, with better results for the lateral and ventrodorsal positions. After the loss of BLSE, bacterial quantification was performed, and Swiss Webster mice presented more bacteria in the nasal cavity (approximately 105 CFU) than the other strains. Our results demonstrate that bioluminescent S. aureus allow monitoring of nasal colonization and estimation of the bacterial burden present in live animals until 48 h.
    Keywords:  Staphylococcus aureus nasal colonization; bioluminescent imaging; murine model
    DOI:  https://doi.org/10.1177/00236772231209790
  15. Front Pharmacol. 2024 ;15 1369337
    Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis.
    Tingting Deng, Jiahe Xu, Qiong Wang, Xing Wang, Yi Jiao, Xiaoxue Cao, Qishun Geng, Mengxiao Zhang, Lu Zhao, Cheng Xiao.
      Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.
    Keywords:  autoimmune diseases; curcumin; epigenetic regulation; macrophage polarization; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fphar.2024.1369337
  16. ACS Omega. 2024 Mar 05. 9(9): 10967-10978
    Neutralizing Staphylococcus aureus PAMPs that Trigger Cytokine Release from THP-1 Monocytes.
    Neda Heydarian, Maya Ferrell, Ayesha S Nair, Chase Roedl, Zongkai Peng, Tra D Nguyen, William Best, Karen L Wozniak, Charles V Rice.
      Innate immunity has considerable specificity and can discriminate between individual species of microbes. In this regard, pathogens are "seen" as dangerous to the host and elicit an inflammatory response capable of destroying the microbes. This immune discrimination is achieved by toll-like receptors on host cells recognizing pathogens, such as Staphylococcus aureus, and microbe-specific pathogen-associated molecular pattern (PAMP) molecules, such as lipoteichoic acid (LTA). PAMPs impede wound healing by lengthening the inflammatory phase of healing and contributing to the development of chronic wounds. Preventing PAMPs from triggering the release of inflammatory cytokines will counteract the dysregulation of inflammation. Here, we use ELISA to evaluate the use of cationic molecules branched polyethylenimine (BPEI), PEGylated BPEI (PEG-BPEI), and polymyxin-B to neutralize anionic LTA and lower levels of TNF-α cytokine release from human THP-1 monocytes in a concentration-dependent manner. Additional data collected with qPCR shows that BPEI and PEG-BPEI reduce the expression profile of the TNF-α gene. Similar effects are observed for the neutralization of whole-cell S. aureus bacteria. In vitro cytotoxicity data demonstrate that PEGylation lowers the toxicity of PEG-BPEI (IC50 = 2661 μm) compared to BPEI (IC50 = 853 μM) and that both compounds are orders of magnitude less toxic than the cationic antibiotic polymyxin-B (IC50 = 79 μM). Additionally, the LTA neutralization ability of polymyxin-B is less effective than BPEI or PEG-BPEI. These properties of BPEI and PEG-BPEI expand their utility beyond disabling antibiotic resistance mechanisms and disrupting S. aureus biofilms, providing additional justification for developing these agents as wound healing therapeutics. The multiple mechanisms of action for BPEI and PEG-BPEI are superior to current wound treatment strategies that have a single modality.
    DOI:  https://doi.org/10.1021/acsomega.4c00043
  17. Front Immunol. 2024 ;15 1382536
    Editorial: Innovative approaches to immune tolerance and regulation with gene, cellular, protein, and microbiome based therapeutics.
    Amy Rosenberg, Dawn Elaine Smilek.
      
    Keywords:  GRAIL; Treg - regulatory T cell; cellular; microbiome; tolerance
    DOI:  https://doi.org/10.3389/fimmu.2024.1382536
  18. bioRxiv. 2024 Feb 29. pii: 2024.02.26.582124. [Epub ahead of print]
    The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.
    Arijit Chakraborty, Arunava Bandyopadhaya, Vijay K Singh, Filip Kovacic, Sujin Cha, William M Oldham, Aria A Tzika, Laurence G Rahme.
      How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages' mitochondrial respiration and bioenergetics. We found that the 2-AA tolerization impairs oxidative phosphorylation (OXPHOS), leading to decreased generation of the crucial energy metabolite ATP and histone acetylation acetyl-CoA. We provide evidence that these effects result from reduced pyruvate flux into mitochondria due to the decreased expression of the mitochondrial pyruvate carrier (MPC1) mediated via the reduced expression and nuclear presence of its transcriptional regulator estrogen-related nuclear receptor (ERRα), leading to the weaker binding of ERRα to MPC1 promoter. This is the outcome of the hampered interaction of ERRα with the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that ultimately leads to reduced pyruvate flux into mitochondria and ATP production in tolerized macrophages. Exogenously added ATP in 2-AA exposed macrophages restores the transcript levels of MPC1 and ERR-α and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic impairment and PA persistence. These findings unveil 2-AA as a negative modulator of cellular immunometabolism implicating the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These findings shed light on the underlying mechanisms of host tolerance and on potential therapeutic strategies to combat persistent PA infections.
    DOI:  https://doi.org/10.1101/2024.02.26.582124
  19. Int J Mol Sci. 2024 Feb 24. pii: 2655. [Epub ahead of print]25(5):
    Molecular Aspects of the Functioning of Pathogenic Bacteria Biofilm Based on Quorum Sensing (QS) Signal-Response System and Innovative Non-Antibiotic Strategies for Their Elimination.
    Edyta Juszczuk-Kubiak.
      One of the key mechanisms enabling bacterial cells to create biofilms and regulate crucial life functions in a global and highly synchronized way is a bacterial communication system called quorum sensing (QS). QS is a bacterial cell-to-cell communication process that depends on the bacterial population density and is mediated by small signalling molecules called autoinducers (AIs). In bacteria, QS controls the biofilm formation through the global regulation of gene expression involved in the extracellular polymeric matrix (EPS) synthesis, virulence factor production, stress tolerance and metabolic adaptation. Forming biofilm is one of the crucial mechanisms of bacterial antimicrobial resistance (AMR). A common feature of human pathogens is the ability to form biofilm, which poses a serious medical issue due to their high susceptibility to traditional antibiotics. Because QS is associated with virulence and biofilm formation, there is a belief that inhibition of QS activity called quorum quenching (QQ) may provide alternative therapeutic methods for treating microbial infections. This review summarises recent progress in biofilm research, focusing on the mechanisms by which biofilms, especially those formed by pathogenic bacteria, become resistant to antibiotic treatment. Subsequently, a potential alternative approach to QS inhibition highlighting innovative non-antibiotic strategies to control AMR and biofilm formation of pathogenic bacteria has been discussed.
    Keywords:  antimicrobial resistance (AMR); autoinducers (AIs); bacterial pathogens; biofilm formation; innovative antibiofilm strategies; quorum quenching (QQ); quorum sensing (QS)
    DOI:  https://doi.org/10.3390/ijms25052655
  20. J Clin Invest. 2024 Jan 11. pii: e172095. [Epub ahead of print]134(6):
    TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.
    Danielle A Callaway, Ian J Penkala, Su Zhou, Jonathan J Knowlton, Fabian Cardenas-Diaz, Apoorva Babu, Michael P Morley, Mariana Lopes, Benjamin A Garcia, Edward E Morrisey.
      Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.
    Keywords:  Extracellular matrix; Integrins; Pulmonology; Respiration
    DOI:  https://doi.org/10.1172/JCI172095
  21. Cell Host Microbe. 2024 Mar 13. pii: S1931-3128(24)00049-0. [Epub ahead of print]32(3): 300-301
    Invade to evade: E. coli's gutsy survival strategies.
    Yuval Mulla, Tobias Bollenbach.
      Antibiotic resistance is often studied in vitro, limiting the understanding of in vivo mechanisms that affect antibiotic treatment. In this issue of Cell Host & Microbe, Rodrigues et al. show that specific mutations allow bacteria to invade intestinal cells in a mouse model, thereby evading antibiotic treatment.
    DOI:  https://doi.org/10.1016/j.chom.2024.02.006
  22. Respir Med. 2024 Mar 07. pii: S0954-6111(24)00060-X. [Epub ahead of print]225 107586
    Chronic obstructive pulmonary disease and the airway microbiome: A review for clinicians.
    Lingxin Luo, Junli Tang, Xianzhi Du, Na Li.
      Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous disease characterized by progressive airflow limitation and chronic inflammation. The progressive development and long-term repeated acute exacerbation of COPD make many patients still unable to control the deterioration of the disease after active treatment, and even eventually lead to death. An increasing number of studies have shown that the occurrence and development of COPD are closely related to the composition and changes of airway microbiome. This article reviews the interaction between COPD and airway microbiome, the potential mechanisms of interaction, and the treatment methods related to microbiome. We elaborated the internal correlation between airway microbiome and different stages of COPD, inflammatory endotypes, glucocorticoid and antibiotic treatment, analyze the pathophysiological mechanisms such as the "vicious cycle" hypothesis, abnormal inflammation-immune response of the host and the "natural selection" of COPD to airway microbiome, introduce the treatment of COPD related to microbiome and emphasize the predictive value of airway microbiome for the progression, exacerbation and prognosis of COPD, as well as the guiding role for clinical management of patients, in order to provide a new perspective for exploring the pathogenesis of COPD, and also provide clues and guidance for finding new treatment targets.
    Keywords:  Chronic obstructive pulmonary disease; Dysbiosis; Infection; Inflammation; Pulmonary microbiome
    DOI:  https://doi.org/10.1016/j.rmed.2024.107586
  23. Inflammation. 2024 Mar 14.
    Pyruvate Kinase M2 Nuclear Translocation Regulate Ferroptosis-Associated Acute Lung Injury in Cytokine Storm.
    Haiting Wang, Chenyu Fan, Xuelian Chen, Wei Zhou, Li Guo, Feng Zhao, Shuang Ye, Shuangjun He, Yi Chen.
      Cytokine storm (CS) is linked with macrophage dysfunction and acute lung injury (ALI), which can lead to patient mortality. Glycolysis is preferentially exploited by the pro-inflammatory macrophages, in which pyruvate kinase M2 (PKM2) is a critical enzyme. The mechanism underlying the link between CS and ALI involves cell death, with the recently discovered programmed cell death known as ferroptosis being involved. However, the relationship between the glycolysis and ferroptosis in the context of CS-related ALI remains unclear. CS-associated ALI induced by poly I:C (10 mg/kg, i.v) and LPS (5 mg/kg, i.p) (IC: LPS) exhibit significant ferroptosis. Ferrostatin-1 (ferroptosis inhibitor) treatment attenuated IC:LPS‑induced mortality and lung injury. Moreover, Alveolar macrophage (AM) from IC:LPS model exhibited enhanced glycolysis and PKM2 translocation. The administration of ML-265(PKM2 monomer/dimer inhibitor) resulted in the formation of a highly active tetrameric PKM2, leading to improved survival and attenuation of ALI. Furthermore, ML-265 treatment decreased ferroptosis and restored the balance between anaerobic glycolysis and oxidative phosphorylation. Notably, in patients with lung infection, intracellular expression level of PKM2 were correlated with circulating inflammation. Enhanced ferroptosis and PKM2 nuclear translocation was noticed in CD14+ blood monocytes of lung infection patients with CS. In conclusion, PKM2 is a key regulatory node integrating metabolic reprograming with intra-nuclear function for the regulation of ferroptosis. Targeting PKM2 could be explored as a potential means in the future to prevent or alleviate hyper-inflammatory state or cytokines storm syndrome with aberrant ferroptotic cell death.
    Keywords:  acute lung injury; cytokine storm; ferroptosis; pyruvate kinase M2
    DOI:  https://doi.org/10.1007/s10753-024-02000-x
  24. Front Immunol. 2024 ;15 1362459
    How do sphingosine-1-phosphate affect immune cells to resolve inflammation?
    Gehui Sun, Bin Wang, Xiaoyu Wu, Jiangfeng Cheng, Junming Ye, Chunli Wang, Hongquan Zhu, Xiaofeng Liu.
      Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development.
    Keywords:  S1P; SphKs; immune cells; inflammation; signal pathway
    DOI:  https://doi.org/10.3389/fimmu.2024.1362459
  25. Rhinology. 2024 Mar 13.
    Eosinophils are the dominant type2 marker for the current indication of biological treatment in severe uncontrolled chronic rhinosinusitis with nasal polyps.
    R van der Lans, J J Otten, G F J P M Adriaensen, L B L Benoist, M E Cornet, D R Hoven, A B Rinia, W J Fokkens, S Reitsma.
      The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) defines markers for type2 inflammation in the context of indicating biological therapy in severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) as either a total serum immunoglobulin E (total-IgE) >100 kU/L, a blood eosinophil count (BEC, expressed as ·109 cells / L) ≥0.25, or a tissue eosinophil count ≥10 per high power field (HPF) (1). Recently, an EPOS/EUFOREA expert panel advised to lower the threshold for BEC from ≥0.25 (EPOS2020) to ≥0.15 (EUFOREA2023) to align with thresholds used for biological indication in asthma patients (2). As far as we know, there is no literature supporting the cut-off value for total-IgE.
    DOI:  https://doi.org/10.4193/Rhin23.081
  26. Eur Respir J. 2024 Mar 14. pii: 2302290. [Epub ahead of print]
    The Longitudinal Microbial and Metabolic Landscape of infant Cystic Fibrosis: The gut-lung axis.
    SYNERGY CF
      BACKGROUND AND AIM: : In cystic fibrosis (CF), gastrointestinal dysfunction and lower airway infection occur early and are independently associated with poorer outcomes in childhood. This study aimed to define the relationship between the microbiota at each niche during the first 2-years of life, its association with growth and airway inflammation, and explanatory features in the metabolome.MATERIALS AND METHODS: Sixty-seven bronchoalveolar lavage (BAL), 62 plasma and 105 stool samples were collected from 39 infants with CF between 0-24-months who were treated with prophylactic antibiotics. 16S rRNA amplicon and shotgun metagenomic sequencing were performed on BAL and stool respectively; metabolomic analyses were performed on all sample types. Sequencing data from healthy age-matched infants were used as controls.
    RESULTS: Bacterial diversity increased over the first 2-years in both BAL and stool, and microbial maturation was delayed in comparison to healthy controls from the RESONANCE cohort. Correlations between their respective abundances in both sites suggest stool may serve as a non-invasive alternative for detecting BAL Pseudomonas and Veillonella. Multi-site metabolomic analyses revealed age- and growth-related changes, associations with neutrophilic airway inflammation, and a set of core systemic metabolites. BAL Pseudomonas abundance was correlated with altered stool microbiome composition and systemic metabolite alterations, highlighting a complex gut-plasma-lung interplay and new targets with therapeutic potential.
    CONCLUSION: Exploration of the gut-lung microbiome and metabolome reveals diverse multi-site interactions in CF that emerge in early life. Gut-lung metabolomic links with airway inflammation and Pseudomonas abundance warrant further investigation for clinical utility, particularly in non-expectorating patients.
    DOI:  https://doi.org/10.1183/13993003.02290-2023
  27. Sci Rep. 2024 03 12. 14(1): 5966
    Quantitative proteomics reveals tissue-specific, infection-induced and species-specific neutrophil protein signatures.
    Gabriel Sollberger, Alejandro J Brenes, Jordan Warner, J Simon C Arthur, Andrew J M Howden.
      Neutrophils are one of the first responders to infection and are a key component of the innate immune system through their ability to phagocytose and kill invading pathogens, secrete antimicrobial molecules and produce extracellular traps. Neutrophils are produced in the bone marrow, circulate within the blood and upon immune challenge migrate to the site of infection. We wanted to understand whether this transition shapes the mouse neutrophil protein landscape, how the mouse neutrophil proteome is impacted by systemic infection and perform a comparative analysis of human and mouse neutrophils. Using quantitative mass spectrometry we reveal tissue-specific, infection-induced and species-specific neutrophil protein signatures. We show a high degree of proteomic conservation between mouse bone marrow, blood and peritoneal neutrophils, but also identify key differences in the molecules that these cells express for sensing and responding to their environment. Systemic infection triggers a change in the bone marrow neutrophil population with considerable impact on the core machinery for protein synthesis and DNA replication along with environmental sensors. We also reveal profound differences in mouse and human blood neutrophils, particularly their granule contents. Our proteomics data provides a valuable resource for understanding neutrophil function and phenotypes across species and model systems.
    DOI:  https://doi.org/10.1038/s41598-024-56163-6
  28. Front Cell Infect Microbiol. 2024 ;14 1342913
    Strategies of Helicobacter pylori in evading host innate and adaptive immunity: insights and prospects for therapeutic targeting.
    Jiawei Fan, Jianshu Zhu, Hong Xu.
      Helicobacter pylori (H. pylori) is the predominant pathogen causing chronic gastric mucosal infections globally. During the period from 2011 to 2022, the global prevalence of H. pylori infection was estimated at 43.1%, while in China, it was slightly higher at approximately 44.2%. Persistent colonization by H. pylori can lead to gastritis, peptic ulcers, and malignancies such as mucosa-associated lymphoid tissue (MALT) lymphomas and gastric adenocarcinomas. Despite eliciting robust immune responses from the host, H. pylori thrives in the gastric mucosa by modulating host immunity, particularly by altering the functions of innate and adaptive immune cells, and dampening inflammatory responses adverse to its survival, posing challenges to clinical management. The interaction between H. pylori and host immune defenses is intricate, involving evasion of host recognition by modifying surface molecules, manipulating macrophage functionality, and modulating T cell responses to evade immune surveillance. This review analyzes the immunopathogenic and immune evasion mechanisms of H. pylori, underscoring the importance of identifying new therapeutic targets and developing effective treatment strategies, and discusses how the development of vaccines against H. pylori offers new hope for eradicating such infections.
    Keywords:  Helicobacter pylori; adaptive immunity; immune evasion; microRNA; vaccination
    DOI:  https://doi.org/10.3389/fcimb.2024.1342913
  29. Front Cell Infect Microbiol. 2024 ;14 1373846
    Editorial: Antibiotics overuse as the driving force behind antimicrobial resistance.
    Liran Shani, Israel Nissan.
      
    Keywords:  AMR (antimicrobial resistance); antibiotics overuse; antibiotics resistance; antibiotics stewardship; resistant bacteria
    DOI:  https://doi.org/10.3389/fcimb.2024.1373846
  30. Int J Cancer. 2024 Mar 14.
    Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity.
    Aline Atallah, Arielle Grossman, Richard W Nauman, Jean-François Paré, Adam Khan, D Robert Siemens, Tiziana Cotechini, Charles H Graham.
      Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.
    Keywords:  BCG; bladder cancer; immune microenvironment; systemic immunity; trained immunity
    DOI:  https://doi.org/10.1002/ijc.34897
  31. Immunity. 2024 Mar 12. pii: S1074-7613(24)00087-6. [Epub ahead of print]57(3): 429-445
    Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases.
    Kate E Lawlor, James M Murphy, James E Vince.
      Diverse inflammatory conditions, from infections to autoimmune disease, are often associated with cellular damage and death. Apoptotic cell death has evolved to minimize its inflammatory potential. By contrast, necrotic cell death via necroptosis and pyroptosis-driven by membrane-damaging MLKL and gasdermins, respectively-can both initiate and propagate inflammatory responses. In this review, we provide insights into the function and regulation of MLKL and gasdermin necrotic effector proteins and drivers of plasma membrane rupture. We evaluate genetic evidence that MLKL- and gasdermin-driven necrosis may either provide protection against, or contribute to, disease states in a context-dependent manner. These cumulative insights using gene-targeted mice underscore the necessity for future research examining pyroptotic and necroptotic cell death in human tissue, as a basis for developing specific necrotic inhibitors with the potential to benefit a spectrum of pathological conditions.
    Keywords:  GSDMD; GSDME; MLKL; NINJ1; RIPK3; caspase-1; gasdermin; inflammasome; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1016/j.immuni.2024.02.011
  32. bioRxiv. 2024 Mar 04. pii: 2024.02.27.582348. [Epub ahead of print]
    Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis.
    Kimberly A Dill-McFarland, Jason D Simmons, Glenna J Peterson, Felicia K Nguyen, Monica Campo, Penelope Benchek, Catherine M Stein, Tomas Vaisar, Harriet Mayanja-Kizza, W Henry Boom, Thomas R Hawn.
      Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon gamma release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. In contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid and cholesterol associated pathways including in the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived HDL from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.
    DOI:  https://doi.org/10.1101/2024.02.27.582348
  33. Proc Natl Acad Sci U S A. 2024 Mar 19. 121(12): e2312404121
    A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane-bound and soluble BDCA-2.
    Francisco Venegas-Solis, Laura Staliunaite, Elisa Rudolph, Carina Chan-Song Münch, Philipp Yu, Sven-A Freibert, Takahiro Maeda, Christine L Zimmer, Christian Möbs, Christian Keller, Andreas Kaufmann, Stefan Bauer.
      Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.
    Keywords:  BDCA-2; glycosaminoglycans; heparin; plasmacytoid dendritic cells; type I interferons
    DOI:  https://doi.org/10.1073/pnas.2312404121
  34. Clin Infect Dis. 2024 Mar 11. pii: ciae126. [Epub ahead of print]
    The positioning of ceftobiprole in the treatment of Staphylococcus aureus bacteremia.
    Daniel J Minter, Ayesha Appa, Henry F Chambers, Sarah B Doernberg.
      
    DOI:  https://doi.org/10.1093/cid/ciae126
  35. Clin Transl Allergy. 2024 Mar;14(3): e12347
    Delayed neutrophil shedding of CD62L in patients with chronic rhinosinusitis with nasal polyps and asthma: Implications for Staphylococcus aureus colonization and corticosteroid treatment.
    Maryam Jafari, Eduardo I Cardenas, Sandra Ekstedt, Julia Arebro, Marianne Petro, Agnetha Karlsson, Eric Hjalmarsson, Daniel Arnarson, Monika Ezerskyte, Susanna Kumlien Georén, Lars Olaf Cardell.
      
    DOI:  https://doi.org/10.1002/clt2.12347
  36. Cell Commun Signal. 2024 Mar 09. 22(1): 172
    The role of macrophage polarization and cellular crosstalk in the pulmonary fibrotic microenvironment: a review.
    Bo-Wen Zhou, Hua-Man Liu, Fei Xu, Xin-Hua Jia.
      Pulmonary fibrosis (PF) is a progressive interstitial inflammatory disease with a high mortality rate. Patients with PF commonly experience a chronic dry cough and progressive dyspnoea for years without effective mitigation. The pathogenesis of PF is believed to be associated with dysfunctional macrophage polarization, fibroblast proliferation, and the loss of epithelial cells. Thus, it is of great importance and necessity to explore the interactions among macrophages, fibroblasts, and alveolar epithelial cells in lung fibrosis, as well as in the pro-fibrotic microenvironment. In this review, we discuss the latest studies that have investigated macrophage polarization and activation of non-immune cells in the context of PF pathogenesis and progression. Next, we discuss how profibrotic cellular crosstalk is promoted in the PF microenvironment by multiple cytokines, chemokines, and signalling pathways. And finally, we discuss the potential mechanisms of fibrogenesis development and efficient therapeutic strategies for the disease. Herein, we provide a comprehensive summary of the vital role of macrophage polarization in PF and its profibrotic crosstalk with fibroblasts and alveolar epithelial cells and suggest potential treatment strategies to target their cellular communication in the microenvironment.
    Keywords:  Alveolar epithelial cell; Crosstalk; Fibroblast; Macrophage polarization; PF
    DOI:  https://doi.org/10.1186/s12964-024-01557-2
  37. Int Immunopharmacol. 2024 Mar 13. pii: S1567-5769(24)00339-4. [Epub ahead of print]131 111821
    IFNγ insufficiency during mouse intra-vaginal Chlamydia trachomatis infection exacerbates alternative activation in macrophages with compromised CD40 functions.
    Naveen Challagundla, Dhruvi Shah, Sarat K Dalai, Reena Agrawal-Rajput.
      Chlamydia trachomatis (C.tr), an obligate intracellular pathogen, causes asymptomatic genital infections in women and is a leading cause of preventable blindness. We have developed in vivo mouse models of acute and chronic C. trachomatis genital infection to explore the significance of macrophage-directed response in mediating immune activation/suppression. Our findings reveal that during chronic and repeated C. trachomatis infections, Th1 response is abated while Treg response is enhanced. Additionally, an increase in exhaustion (PD1, CTLA4) and anergic (Klrg3, Tim3) T cell markers is observed during chronic infection. We have also observed that M2 macrophages with low CD40 expression promote Th2 and Treg differentiation leading to sustained C. trachomatis genital infection. Macrophages infected with C. trachomatis or treated with supernatant of infected epithelial cells drive them to an M2 phenotype. C. trachomatis infection prevents the increase in CD40 expression as observed in western blots and flow cytometric analysis. Insufficient IFNγ, as observed during chronic infection, leads to incomplete clearance of bacteria and poor immune activation. C. trachomatis decapacitates IFNγ responsiveness in macrophages via hampering IFNγRI and IFNγRII expression which can be correlated with poor expression of MHC-II, CD40, iNOS and NO release even following IFNγ supplementation. M2 macrophages during C. trachomatis infection express low CD40 rendering immunosuppressive, Th2 and Treg differentiation which could not be reverted even by IFNγ supplementation. The alternative macrophages also harbour high bacterial load and are poor responders to IFNγ, thus promoting immunosuppression. In summary, C. trachomatis modulates the innate immune cells, attenuating the anti-chlamydial functions of T cells in a manner that involves decreased CD40 expression on macrophages.
    Keywords:  C. trachomatis; CD40; IFNγ; Immunosuppression; Macrophage polarization
    DOI:  https://doi.org/10.1016/j.intimp.2024.111821
  38. Curr Opin Clin Nutr Metab Care. 2024 Mar 11.
    Microbiome and its impact on fetal and neonatal brain development: current opinion in pediatrics.
    Nina M Frerichs, Tim G J de Meij, Hendrik J Niemarkt.
      PURPOSE OF REVIEW: Emerging evidence suggests that the gut microbiota and its metabolites regulate neurodevelopment and cognitive functioning via a bi-directional communication system known as the microbiota-gut-brain axis (MGBA).RECENT FINDINGS: The MGBA influences brain development and function via the hypothalamic-pituitary axis, the vagal nerve, immune signaling, bacterial production of neurotransmitters, and microbial metabolites like short-chain fatty acids, tryptophan derivatives, and bile acids. Animal studies show fetal neurodevelopment is mediated by maternal microbiota derivatives, immune activation, and diet. Furthermore, manipulation of the microbiota during critical windows of development, like antibiotic exposure and fecal microbiota transplantation, can affect cognitive functioning and behavior in mice. Evidence from human studies, particularly in preterm infants, also suggests that a disrupted gut microbiota colonization may negatively affect neurodevelopment. Early microbial signatures were linked to favorable and adverse neurodevelopmental outcomes.
    SUMMARY: The link between the gut microbiota and the brain is evident. Future studies, including experimental studies, larger participant cohort studies with longitudinal analyses of microbes, their metabolites, and neurotransmitters, and randomized controlled trials are warranted to further elucidate the mechanisms of the MGBA. Identification of early, predictive microbial markers could pave the way for the development of novel early microbiota-based intervention strategies, such as targeted probiotics, and vaginal or fecal microbiota transplantation, aimed at improving infant neurodevelopment.
    DOI:  https://doi.org/10.1097/MCO.0000000000001028
  39. bioRxiv. 2024 Mar 03. pii: 2024.02.28.582578. [Epub ahead of print]
    Krüppel-like Factor (KLF) family members control expression of genes required for serous cavity and alveolar macrophage identities.
    Kathleen Pestal, Leianna C Slayden, Gregory M Barton.
      Tissue-resident macrophages adopt distinct gene expression profiles and exhibit functional specialization based on their tissue of residence. Recent studies have begun to define the signals and transcription factors that induce these identities. Here we describe an unexpected and specific role for the broadly expressed transcription factor Kruppel-like Factor 2 (KLF2) in the development of embryonically derived Large Cavity Macrophages (LCM) in the serous cavities. KLF2 not only directly regulates the transcription of genes previously shown to specify LCM identity, such as retinoic acid receptors and GATA6, but also is required for induction of many other transcripts that define the identity of these cells. We identify a similar role for KLF4 in regulating the identity of alveolar macrophages in the lung. These data demonstrate that broadly expressed transcription factors, such as Group 2 KLFs, can play important roles in the specification of distinct identities of tissue-resident macrophages.SUMMARY: Previous studies have identified many specific regulators of macrophage development. This work reveals the requirement of members of the Group 2 KLF transcription factor family in the determination of the identity of distinct tissue-resident macrophages.
    DOI:  https://doi.org/10.1101/2024.02.28.582578
  40. Front Immunol. 2024 ;15 1349500
    VEGFR-3 signaling in macrophages: friend or foe in disease?
    Saranya Kannan, Joseph M Rutkowski.
      Lymphatic vessels have been increasingly appreciated in the context of immunology not only as passive conduits for immune and cancer cell transport but also as key in local tissue immunomodulation. Targeting lymphatic vessel growth and potential immune regulation often takes advantage of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling to manipulate lymphatic biology. A receptor tyrosine kinase, VEGFR-3, is highly expressed on lymphatic endothelial cells, and its signaling is key in lymphatic growth, development, and survival and, as a result, often considered to be "lymphatic-specific" in adults. A subset of immune cells, notably of the monocyte-derived lineage, have been identified to express VEGFR-3 in tissues from the lung to the gut and in conditions as varied as cancer and chronic kidney disease. These VEGFR-3+ macrophages are highly chemotactic toward the VEGFR-3 ligands VEGF-C and VEGF-D. VEGFR-3 signaling has also been implicated in dictating the plasticity of these cells from pro-inflammatory to anti-inflammatory phenotypes. Conversely, expression may potentially be transient during monocyte differentiation with unknown effects. Macrophages play critically important and varied roles in the onset and resolution of inflammation, tissue remodeling, and vasculogenesis: targeting lymphatic vessel growth and immunomodulation by manipulating VEGFR-3 signaling may thus impact macrophage biology and their impact on disease pathogenesis. This mini review highlights the studies and pathologies in which VEGFR-3+ macrophages have been specifically identified, as well as the activity and polarization changes that macrophage VEGFR-3 signaling may elicit, and affords some conclusions as to the importance of macrophage VEGFR-3 signaling in disease.
    Keywords:  FLT4/VEGFR3; M1 macrophage; M2 macrophage; VEGFC/D-VEGFR3/NRP2 axis; lymphangiogenesis; monocyte
    DOI:  https://doi.org/10.3389/fimmu.2024.1349500
  41. Front Immunol. 2024 ;15 1360716
    Abnormal functional lymphoid tolerance and enhanced myeloid exocytosis are characteristics of resting and stimulated PBMCs in cystic fibrosis patients.
    Clémence Gaudin, Reem Ghinnagow, Flora Lemaire, Bérengère Villeret, Isabelle Sermet-Gaudelus, Jean-Michel Sallenave.
      Introduction: Cystic Fibrosis (CF) is the commonest genetically inherited disease (1 in 4,500 newborns) and 70% of people with CF (pwCF) harbour the F508Del mutation, resulting in misfolding and incorrect addressing of the channel CFTR to the epithelial membrane and subsequent dysregulation of fluid homeostasis. Although studies have underscored the importance and over-activation of myeloid cells, and in particular neutrophils in the lungs of people with CF (pwCF), relatively less emphasis has been put on the potential immunological bias in CF blood cells, at homeostasis or following stimulation/infection.Methods: Here, we revisited, in an exhaustive fashion, in pwCF with mild disease (median age of 15, median % FEV1 predicted = 87), whether their PBMCs, unprimed or primed with a 'non specific' stimulus (PMA+ionomycin mix) and a 'specific' one (live P.a =PAO1 strain), were differentially activated, compared to healthy controls (HC) PBMCs.
    Results: 1) we analysed the lymphocytic and myeloid populations present in CF and Control PBMCs (T cells, NKT, Tgd, ILCs) and their production of the signature cytokines IFN-g, IL-13, IL-17, IL-22. 2) By q-PCR, ELISA and Luminex analysis we showed that CF PBMCs have increased background cytokines and mediators production and a partial functional tolerance phenotype, when restimulated. 3) we showed that CF PBMCs low-density neutrophils release higher levels of granule components (S100A8/A9, lactoferrin, MMP-3, MMP-7, MMP-8, MMP-9, NE), demonstrating enhanced exocytosis of potentially harmful mediators.
    Discussion: In conclusion, we demonstrated that functional lymphoid tolerance and enhanced myeloid protease activity are key features of cystic fibrosis PBMCs.
    Keywords:  PBMCs; Pseudomonas aeruginosa; cystic fibrosis; low-density neutrophils; lymphocyte; proteases; tolerance
    DOI:  https://doi.org/10.3389/fimmu.2024.1360716
  42. Cell Host Microbe. 2024 Mar 13. pii: S1931-3128(24)00052-0. [Epub ahead of print]32(3): 293-295
    A new piece of the microbiota pie: Mining 'omics for DNA inversion states.
    Danielle E Campbell, Megan T Baldridge.
      In this issue of Cell Host & Microbe, Carasso et al. survey invertible DNA sites in Bacteroidales from patients with inflammatory bowel disease (IBD) and healthy control individuals. They identify complex functional interactions between Bacteroides fragilis, an invertible promoter, a capsular polysaccharide, a bacteriophage, and the human host. The establishment of 'omics approaches to characterizing genomic targets and functional roles is still required.
    DOI:  https://doi.org/10.1016/j.chom.2024.02.009
  43. Microbiome. 2024 Mar 12. 12(1): 50
    Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases.
    PrediRes study group
      BACKGROUND: Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience.RESULTS: While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools.
    CONCLUSIONS: In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract.
    Keywords:  Antibiotics; Human gut microbiota; Metabolomics; Metagenomics; Resilience; β-lactamase
    DOI:  https://doi.org/10.1186/s40168-023-01746-0
  44. FEBS Lett. 2024 Mar 14.
    Inflammasomes in epithelial innate immunity: front line warriors.
    Kim Samirah Robinson, Dave Boucher.
      Our epithelium represents a battle ground against a variety of insults including pathogens and danger signals. It encodes multiple sensors that detect and respond to such insults, playing an essential role in maintaining and defending tissue homeostasis. One key set of defense mechanisms is our inflammasomes which drive innate immune responses including, sensing and responding to pathogen attack, through the secretion of pro-inflammatory cytokines and cell death. Identification of physiologically relevant triggers for inflammasomes has greatly influenced our ability to decipher the mechanisms behind inflammasome activation. Furthermore, identification of patient mutations within inflammasome components implicates their involvement in a range of epithelial diseases. This review will focus on exploring the roles of inflammasomes in epithelial immunity and cover: the diversity and differential expression of inflammasome sensors amongst our epithelial barriers, their ability to sense local infection and damage and the contribution of the inflammasomes to epithelial homeostasis and disease.
    Keywords:  GBP; GI tract; NLRP1; epithelial barrier; inflammasome; inflammation; innate immunity; skin
    DOI:  https://doi.org/10.1002/1873-3468.14848
  45. Cell Rep. 2024 Mar 12. pii: S2211-1247(24)00290-0. [Epub ahead of print]43(3): 113962
    Pneumococcal sialidase promotes bacterial survival by fine-tuning of pneumolysin-mediated membrane disruption.
    Sayaka Shizukuishi, Michinaga Ogawa, Eisuke Kuroda, Shigeto Hamaguchi, Chisato Sakuma, Soichiro Kakuta, Isei Tanida, Yasuo Uchiyama, Yukihiro Akeda, Akihide Ryo, Makoto Ohnishi.
      Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal vesicles is a prerequisite for the evasion of endolysosomal bacterial clearance, its potent activity can be a double-edged sword, having a detrimental effect on bacterial survivability by inducing severe endosomal disruption, bactericidal autophagy, and scaffold epithelial cell death. Thus, Ply activity must be maintained at optimal levels. We develop a highly sensitive assay to monitor endosomal disruption using NanoBiT-Nanobody, which shows that the pneumococcal sialidase NanA can fine-tune Ply activity by trimming sialic acid from cell-membrane-bound glycans. In addition, oseltamivir, an influenza A virus sialidase inhibitor, promotes Ply-induced endosomal disruption and cytotoxicity by inhibiting NanA activity in vitro and greater tissue damage and bacterial clearance in vivo. Our findings provide a foundation for innovative therapeutic strategies for severe pneumococcal infections by exploiting the duality of Ply activity.
    Keywords:  CP: Cell biology; CP: Microbiology; NanA; NanoBiT; Streptococcus pneumoinae; cytotoxicity; endosome disrupture; nanobody; oseltamivir; pneumolysin; sialic acid; xenophagy
    DOI:  https://doi.org/10.1016/j.celrep.2024.113962
  46. Nature. 2024 Mar 13.
    Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release.
    Turan Tufan, Gamze Comertpay, Ambra Villani, Geoffrey M Nelson, Marina Terekhova, Shannon Kelley, Pavel Zakharov, Rochelle M Ellison, Oleg Shpynov, Michael Raymond, Jerry Sun, Yitan Chen, Enno Bockelmann, Marta Stremska, Lance W Peterson, Laura Boeckaerts, Seth R Goldman, J Iker Etchegaray, Maxim N Artyomov, Francesca Peri, Kodi S Ravichandran.
      During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis1. How macrophages may rapidly adapt their transcription to achieve continuous corpse uptake is incompletely understood. Transcriptional pause/release is an evolutionarily conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20-60 nucleotides, is paused for minutes to hours and is then released to make full-length mRNA2. Here we show that macrophages, within minutes of corpse encounter, use transcriptional pause/release to unleash a rapid transcriptional response. For human and mouse macrophages, the Pol II pause/release was required for continuous efferocytosis in vitro and in vivo. Interestingly, blocking Pol II pause/release did not impede Fc receptor-mediated phagocytosis, yeast uptake or bacterial phagocytosis. Integration of data from three genomic approaches-precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq)-on efferocytic macrophages at different time points revealed that Pol II pause/release controls expression of select transcription factors and downstream target genes. Mechanistic studies on transcription factor EGR3, prominently regulated by pause/release, uncovered EGR3-related reprogramming of other macrophage genes involved in cytoskeleton and corpse processing. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Furthermore, microglia from egr3-deficient zebrafish embryos displayed reduced phagocytosis of apoptotic neurons and fewer maturing phagosomes, supporting defective corpse processing. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.
    DOI:  https://doi.org/10.1038/s41586-024-07172-y
  47. Adv Exp Med Biol. 2024 ;1444 111-127
    Control of the Development, Distribution, and Function of Innate-Like Lymphocytes and Innate Lymphoid Cells by the Tissue Microenvironment.
    Koichi Ikuta, Takuma Asahi, Guangwei Cui, Shinya Abe, Daichi Takami.
      Recently, considerable attention has been directed toward innate-like T cells (ITCs) and innate lymphoid cells (ILCs) owing to their indispensable contributions to immune responses, tissue homeostasis, and inflammation. Innate-like T cells include NKT cells, MAIT cells, and γδ T cells, whereas ILCs include NK cells, type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), and type 3 ILCs (ILC3s). Many of these ITCs and ILCs are distributed to specific tissues and remain tissue-resident, while others, such as NK cells and some γδ T cells, circulate through the bloodstream. Nevertheless, recent research has shed light on novel subsets of innate immune cells that exhibit characteristics intermediate between tissue-resident and circulating states under normal and pathological conditions. The local microenvironment frequently influences the development, distribution, and function of these innate immune cells. This review aims to consolidate the current knowledge on the functional heterogeneity of ITCs and ILCs, shaped by local environmental cues, with particular emphasis on IL-15, which governs the activities of the innate immune cells involved in type 1 immune responses.
    Keywords:  Airway inflammation; Bone marrow; IL-15; IL-7 receptor; ILC1; ILC2; Innate lymphoid cell (ILC); Innate-like T cell; NKT cell; Tissue-resident
    DOI:  https://doi.org/10.1007/978-981-99-9781-7_8
  48. Am J Clin Nutr. 2024 Mar 08. pii: S0002-9165(24)00340-X. [Epub ahead of print]
    Efficacy and safety of a synbiotic infant formula for the prevention of respiratory and gastrointestinal infections: A randomized controlled trial.
    GOLF III Study Group
      BACKGROUND: Early life nutrition is crucial for the development of the gut microbiota that, in turn, plays an essential role in the maturation of the immune system and the prevention of infections.OBJECTIVES: The aim of this study was to investigate whether feeding synbiotic infant and follow-on formulas during the first year of life reduces the incidence rate (IR) of infectious diarrhea compared to standard formulas. Secondary endpoints included the IR of other infectious diseases as well as fecal milieu parameters.
    METHODS: In this double-blind, controlled trial, 460 healthy, 1-month old infants were randomized to receive a synbiotic (galacto-oligosaccharides (GOS) / Limosilactobacillus fermentum CECT 5716) (IF, n=230) or a control formula (CF, n=230) until 12 months of age. A reference group of breastfed infants (HM, n=80) was included. Data on infections were recorded throughout the study period and stool samples were collected at 4 and 12 months of age.
    RESULTS: IR of infectious diarrhea during the first year of life was 0.60 (CF), 0.56 (IF) and 0.29 (HM) with no statistically significant difference between groups. The IR of lower respiratory tract infections, one of the secondary endpoints, however, was lower in IF than in CF (0.79 versus 1.01, IR ratio = 0.77 (0.60,1.00)). Additionally, fecal pH was significantly lower at 4 months (p<0.0001), while secretory IgA was significantly higher at 12 months of age (p=0.015) in IF compared to CF.
    CONCLUSIONS: Although no difference was observed in the incidence of diarrhea, consumption of a synbiotic formula containing L. fermentum CECT5716 and GOS in infancy may reduce the incidence of lower respiratory tract infections and affect the immune system and fecal milieu. Additional research is warranted to further investigate the potential interaction of the gut-lung axis.
    CLINICAL TRIALS REGISTRY NUMBER: NCT02221687 (https://clinicaltrials.gov/ct2/show/NCT02221687).
    Keywords:  GOS; Limosilactobacillus fermentum; formula; gut microbiota; gut-lung-axis; infant; infections; respiratory tract; synbiotic
    DOI:  https://doi.org/10.1016/j.ajcnut.2024.03.005
  49. Heliyon. 2024 Mar 15. 10(5): e27480
    Innate immune cells: Key players of orchestra in modulating tumor microenvironment (TME).
    Mahvash Sadeghi, Sajad Dehnavi, Moosa Sharifat, Amir Mohammad Amiri, Ali Khodadadi.
      The tumor microenvironment (TME) with vital role in cancer progression is composed of various cells such as endothelial cells, immune cells, and mesenchymal stem cells. In particular, innate immune cells such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, innate lymphoid cells, γδT lymphocytes, and natural killer cells can either promote or suppress tumor progression when present in the TME. An increase in research on the cross-talk between the TME and innate immune cells will lead to new approaches for anti-tumoral therapeutic interventions. This review primarily focuses on the biology of innate immune cells and their main functions in the TME. In addition, it summarizes several innate immune-based immunotherapies that are currently tested in clinical trials.
    Keywords:  Anti-tumor treatment; Immunotherapy; Innate immune cells; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e27480
  50. Life Sci. 2024 Mar 08. pii: S0024-3205(24)00041-9. [Epub ahead of print] 122452
    The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis.
    Xiaohui Hu, Xinyi Yuan, Guokun Zhang, Haoyun Song, Pengfei Ji, Yanan Guo, Zihua Liu, Yixiao Tian, Rong Shen, Degui Wang.
      The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
    Keywords:  Disease prevention and treatment; Immunomodulation; Injury repair; Intestinal epithelial cell homeostasis; Macrophages mediate crypt stem cell proliferation
    DOI:  https://doi.org/10.1016/j.lfs.2024.122452
  51. Clin Transl Med. 2024 Mar;14(3): e1618
    Implications of blood type in personalised microbiome therapy.
    Yue Zhang, Ranko Gacesa, Jingyuan Fu.
      
    DOI:  https://doi.org/10.1002/ctm2.1618
  52. J Adv Res. 2024 Mar 07. pii: S2090-1232(24)00088-2. [Epub ahead of print]
    The epidermal lipid-microbiome loop and immunity: Important players in atopic dermatitis.
    Junchao Wu, Lisha Li, Tingrui Zhang, Jiaye Lu, Zongguang Tai, Quangang Zhu, Zhongjian Chen.
      BACKGROUND: The promotion of epidermal barrier dysfunction is attributed to abnormalities in the lipid-microbiome positive feedback loop which significantly influences the imbalance of the epithelial immune microenvironment (EIME) in atopic dermatitis (AD). This imbalance encompasses impaired lamellar membrane integrity, heightened exposure to epidermal pathogens, and the regulation of innate and adaptive immunity. The lipid-microbiome loop is substantially influenced by intense adaptive immunity which is triggered by abnormal loop activity and affects the loop's integrity through the induction of atypical lipid composition and responses to dysregulated epidermal microbes. Immune responses participate in lipid abnormalities within the EIME by downregulating barrier gene expression and are further cascade-amplified by microbial dysregulation which is instigated by barrier impairment.AIM OF REVIEW: This review examines the relationship between abnormal lipid composition, microbiome disturbances, and immune responses in AD while progressively substantiating the crosstalk mechanism among these factors. Based on this analysis, the "lipid-microbiome" positive feedback loop, regulated by immune responses, is proposed.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: The review delves into the impact of adaptive immune responses that regulate the EIME, driving AD, and investigates potential mechanisms by which lipid supplementation and probiotics may alleviate AD through the up-regulation of the epidermal barrier and modulation of immune signaling. This exploration offers support for targeting the EIME to attenuate AD.
    Keywords:  Adaptive immunity; Atopic dermatitis; Epidermal lipid; Lipid-microbiome loop; Microbe
    DOI:  https://doi.org/10.1016/j.jare.2024.03.001
  53. Exp Ther Med. 2024 Apr;27(4): 157
    Antibiotic administration aggravates asthma by disrupting gut microbiota and the intestinal mucosal barrier in an asthma mouse model.
    Cheng-Ling Xu, Cui Wang, Gao-Bin Li, Tong Zhao, Rui-Ling Zhou, Jing Chen.
      In humans, gut microbiota can determine the health status. The regulatory mechanisms of the gut microbiota in asthma must be elucidated. Although antibiotics (ABXs) can clear infections, they markedly alter the composition and abundance of gut microbiota. The present study used ABX-treated mice to examine the time-dependent effects of ABX administration on the gut microbiota and intestinal mucosal barrier. The mouse asthma model was established using ovalbumin (OVA) and gavaged with an ABX cocktail for different durations (1 or 2 weeks) and stacked sequences. The pathology of the model, model 2, OVA-ABX, OVA-ABX 2, ABX-OVA and ABX-OVA was severe when compared with the control group as evidenced by the following results: i) significantly increased pulmonary and colonic inflammatory cell infiltration; ii) enhanced pause values and iii) OVA-induced immunoglobulin E (IgE) and TGF-β expression levels, and significantly downregulated Tight Junction Protein 1 (TJP1), claudin 1 and Occludin expression levels. Furthermore, the intestinal bacterial load in the OVA-ABX and OVA-ABX 2 groups was significantly lower than that in the ABX-OVA and ABX-OVA 2 groups, respectively. The predominant taxa were as follows: phyla, Firmicutes and Proteobacteria, genera, Escherichia-Shigella, Lactobacillus and Lachnospira. The abundances of Lachnospira and Escherichia-Shigella were correlated with the expression of OVA-induced IgE and TJPs. These findings indicated that ABX administration, which modifies microbiome diversity and bacterial abundance, can disrupt colonic integrity, downregulate TJ proteins, damage the intestinal barrier, enhance enterocyte permeability, and promote the release of inflammatory factors, adversely affecting asthma alleviation and long-term repair.
    Keywords:  asthma; inflammation; intestinal flora; tight junction proteins
    DOI:  https://doi.org/10.3892/etm.2024.12445
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