bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–12–01
fifty-four papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. The immune memory of innate immune systems.
  2. Impact of extracellular enzymes on Staphylococcus aureus host tissue adaptation and infection.
  3. Bacteria and fungi of the lung: allies or enemies?
  4. Card9 and MyD88 differentially regulate Th17 immunity to the commensal yeast Malassezia in the murine skin.
  5. Epigenetic mechanisms of alveolar macrophage activation in chemical-induced acute lung injury.
  6. SARS-CoV-2 reprograms murine alveolar macrophages to dampen flu.
  7. Bacterial single-cell RNA sequencing captures biofilm transcriptional heterogeneity and differential responses to immune pressure.
  8. Mesenchymal stromal cells can block palmitate training of macrophages via cyclooxygenase-2 and interleukin-1 receptor antagonist.
  9. Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
  10. Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications.
  11. The Intriguing Connection Between the Gut and Lung Microbiomes.
  12. Early nasal microbiota and subsequent respiratory tract infections in infants with cystic fibrosis.
  13. Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.
  14. Toll-Like-Receptor 5 protects against pulmonary fibrosis by reducing lung dysbiosis.
  15. Branched-chain amino acid catabolism promotes M2 macrophage polarization.
  16. The tissue glycome as regulator of immune activation and tolerance mediated by C-type lectins and Siglecs.
  17. Influence of Hypoxia on the Airway Epithelium.
  18. Ezrin drives adaptation of monocytes to the inflamed lung microenvironment.
  19. Adaptation in human immune cells residing in tissues at the frontline of infections.
  20. Modulation of the Gut-Lung Axis by Water Kefir and Kefiran and Their Impact on Toll-like Receptor 3-Mediated Respiratory Immunity.
  21. Approaches to investigate tissue-resident innate lymphocytes metabolism at the single-cell level.
  22. Fibroblast-mediated macrophage recruitment supports acute wound healing.
  23. Host metabolic inflammation fueled by bacterial DNA.
  24. Interleukin 1β Mediates the Pathogenesis of Nasal Mucosal Epithelial Barrier Dysfunction in Allergic Rhinitis.
  25. A framework for understanding collective microbiome metabolism.
  26. Unraveling Macrophage Polarization: Functions, Mechanisms, and "Double-Edged Sword" Roles in Host Antiviral Immune Responses.
  27. Sialylated IgG restrains lung inflammation.
  28. Extracellular matrix stiffness facilitates neurite outgrowth by reprogramming the fatty acid oxidation-dependent macrophage polarization.
  29. The bacterial microbiome and cancer: development, diagnosis, treatment, and future directions.
  30. Plasmalogens in Innate Immune Cells: From Arachidonate Signaling to Ferroptosis.
  31. Recent advances in crosstalk between immune cells and cancer cells with ferroptosis.
  32. Microbiota Orchestra in Parkinson's Disease: The Nasal and Oral Maestros.
  33. Cell fusion dynamics: mechanisms of multinucleation in osteoclasts and macrophages.
  34. Immune-Epithelial Cell Interactions in Lung Development, Homeostasis and Disease.
  35. A year of microbiology.
  36. "Microbiome and Hemato-immune Aging".
  37. Intraspecific Diversity of Staphylococcus aureus Populations Isolated from Cystic Fibrosis Respiratory Infections.
  38. Resource landscape shapes the composition and stability of the human vaginal microbiota.
  39. Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming.
  40. The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease.
  41. Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation.
  42. What Does Healthy Microbiome Development Look Like? State of the Art and Beyond.
  43. Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.
  44. Breaking down IgA: Tomasiella immunophila enlightens microbiome-immune interactions.
  45. Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
  46. Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote colonization.
  47. Transcriptional Responses of Lacticaseibacillus rhamnosus to TNFα, IL-6, IL-8, and IL-10 Cytokines.
  48. The interplay between epidermal barrier distribution, microbiota composition, and immune infiltrate defines and stratifies psoriasis patients and is associated with disease severity.
  49. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells.
  50. Ferroptosis in Cancer: Epigenetic Control and Therapeutic Opportunities.
  51. Protection against Clostridioides difficile disease by a naturally avirulent strain.
  52. [Advancements in the regulatory effects and mechanisms of the immune metabolite itaconate in diseases].
  53. Diversity of Neurotransmitter-Producing Human Skin Commensals.
  54. IgA facilitates the persistence of the mucosal pathogen Helicobacter pylori.
  1. Int Immunol. 2024 Nov 26. pii: dxae067. [Epub ahead of print]
    The immune memory of innate immune systems.
    Yasuhiro Kato, Atsushi Kumanogoh.
      Immune memory has long been considered a function specific to adaptive immune systems; however, adaptive immune memory alone has not fully explained the mechanism by which vaccines exert their protective effects against non-target pathogens. Recently, trained immunity, in which human monocytes vaccinated with bacillus Calmette-Guérin become highly responsive to pathogens other than Mycobacterium tuberculosis, has been reported. However, a phenomenon called endotoxin tolerance is also known, in which monocyte responsiveness is attenuated after the first lipopolysaccharide stimulation. These phenomena represent an altered innate immune response after the initial exposure to the stimulus, indicating that memories are formed in the innate immune system. In this review, we discuss trained immunity and endotoxin tolerance, known as innate immune memory, and innate immune memory formation by mRNA vaccines, which have been newly used in the COVID-19 pandemic and are considered important vaccine modalities in the future.
    Keywords:  Endotoxin tolerance; Epigenetic reprogramming; Trained immunity
    DOI:  https://doi.org/10.1093/intimm/dxae067
  2. APMIS. 2024 Nov 27.
    Impact of extracellular enzymes on Staphylococcus aureus host tissue adaptation and infection.
    Atlanta Borah, Anand Srivastava.
      Staphylococcus aureus is a multi-host pathogen that can colonize and infect both humans and livestock in a tissue-specific manner. This amazing feature of the pathogen is mainly facilitated by the surplus virulence agents produced upon necessity and favorable environmental factors. These factors are adept at damaging cellular barriers, manipulating host immune factors, and circumventing the host complement system. The delicate balance between the timely release of virulent factors and the regulation of their production underscores the significance of the exoenzyme network. Moreover, the intricate relationship between the pathogen and host tissue highlights the importance of understanding tissue-specific phenotypes for effective therapeutic strategies. Here, we provide a review on the diverse role played by the extracellular enzymes of S. aureus in tissue-specific infection and systemic colonization leading to distinctive diseased conditions. The article highlights the need to study the role of staphylococcal exoenzymes in various systemic invasions, their impact on the deterioration of host tissue, and the regulation of S. aureus virulence factors.
    Keywords:  Exoenzymes; Staphylococcus aureus; infection; pathogenicity; tissue
    DOI:  https://doi.org/10.1111/apm.13502
  3. Front Pharmacol. 2024 ;15 1497173
    Bacteria and fungi of the lung: allies or enemies?
    Enrico Garaci, Marilena Pariano, Emilia Nunzi, Claudio Costantini, Marina Maria Bellet, Cinzia Antognelli, Matteo Antonio Russo, Luigina Romani.
      Moving from the earlier periods in which the lungs were believed to represent sterile environments, our knowledge on the lung microbiota has dramatically increased, from the first descriptions of the microbial communities inhabiting the healthy lungs and the definition of the ecological rules that regulate its composition, to the identification of the changes that occur in pathological conditions. Despite the limitations of lung as a microbiome reservoir due to the low microbial biomass and abundance, defining its microbial composition and function in the upper and lower airways may help understanding the impact on local homeostasis and its disruption in lung diseases. In particular, the understanding of the metabolic and immune significance of microbes, their presence or lack thereof, in health and disease states could be valuable in development of novel druggable targets in disease treatments. Next-generation sequencing has identified intricate inter-microbe association networks that comprise true mutualistic or antagonistic direct or indirect relationships in the respiratory tract. In this review, the tripartite interaction of bacteria, fungi and the mammalian host is addressed to provide an integrated view of the microbial-host cross-talk in lung health and diseases from an immune and metabolic perspective.
    Keywords:  bacterial-fungal interactions; immunity; metabolism; respiratory bacteriome; respiratory mycobiome
    DOI:  https://doi.org/10.3389/fphar.2024.1497173
  4. Mucosal Immunol. 2024 Nov 21. pii: S1933-0219(24)00112-0. [Epub ahead of print]
    Card9 and MyD88 differentially regulate Th17 immunity to the commensal yeast Malassezia in the murine skin.
    Meret Tuor, Mark H T Stappers, Alice Desgardin, Fiorella Ruchti, Florian Sparber, Selinda J Orr, Neil A R Gow, Salomé LeibundGut-Landmann.
      The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo. In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.
    Keywords:  C type lectin receptors; Cutaneous immunity; Malassezia; Skin commensal yeast; Th17
    DOI:  https://doi.org/10.1016/j.mucimm.2024.11.004
  5. Front Immunol. 2024 ;15 1488913
    Epigenetic mechanisms of alveolar macrophage activation in chemical-induced acute lung injury.
    Shama Ahmad, Wesam Nasser, Aftab Ahmad.
      Airways, alveoli and the pulmonary tissues are the most vulnerable to the external environment including occasional deliberate or accidental exposure to highly toxic chemical gases. However, there are many effective protective mechanisms that maintain the integrity of the pulmonary tissues and preserve lung function. Alveolar macrophages form the first line of defense against any pathogen or chemical/reactant that crosses the airway mucociliary barrier and reaches the alveolar region. Resident alveolar macrophages are activated or circulating monocytes infiltrate the airspace to contribute towards inflammatory or reparative responses. Studies on response of alveolar macrophages to noxious stimuli are rapidly emerging and alveolar macrophage are also being sought as therapeutic target. Here such studies have been reviewed and put together for a better understanding of the role pulmonary macrophages in general and alveolar macrophage in particular play in the pathogenesis of disease caused by chemical induced acute lung injury.
    Keywords:  chemical; epigenetics; halogen; inhaled; lung; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2024.1488913
  6. Trends Immunol. 2024 Nov 22. pii: S1471-4906(24)00273-4. [Epub ahead of print]
    SARS-CoV-2 reprograms murine alveolar macrophages to dampen flu.
    Alexandra Tabachnikova, Akiko Iwasaki.
      Innate immune cells that are epigenetically reprogrammed by infection can modify host responses to subsequent infections. Lercher et al. have identified epigenetic reprogramming of murine airway-resident macrophages following recovery from SARS-CoV-2 infection, conferring protection from pathology and lethality following secondary influenza A virus (IAV) challenge without reducing viral titers.
    DOI:  https://doi.org/10.1016/j.it.2024.11.002
  7. Nat Commun. 2024 Nov 24. 15(1): 10184
    Bacterial single-cell RNA sequencing captures biofilm transcriptional heterogeneity and differential responses to immune pressure.
    Lee E Korshoj, Tammy Kielian.
      Biofilm formation is an important mechanism of survival and persistence for many bacterial pathogens. These multicellular communities contain subpopulations of cells that display metabolic and transcriptional diversity along with recalcitrance to antibiotics and host immune defenses. Here, we present an optimized bacterial single-cell RNA sequencing method, BaSSSh-seq, to study Staphylococcus aureus diversity during biofilm growth and transcriptional adaptations following immune cell exposure. BaSSSh-seq captures extensive transcriptional heterogeneity during biofilm compared to planktonic growth. We quantify and visualize transcriptional regulatory networks across heterogeneous biofilm subpopulations and identify gene sets that are associated with a trajectory from planktonic to biofilm growth. BaSSSh-seq also detects alterations in biofilm metabolism, stress response, and virulence induced by distinct immune cell populations. This work facilitates the exploration of biofilm dynamics at single-cell resolution, unlocking the potential for identifying biofilm adaptations to environmental signals and immune pressure.
    DOI:  https://doi.org/10.1038/s41467-024-54581-8
  8. Cytotherapy. 2024 Oct 31. pii: S1465-3249(24)00905-8. [Epub ahead of print]
    Mesenchymal stromal cells can block palmitate training of macrophages via cyclooxygenase-2 and interleukin-1 receptor antagonist.
    Laura M Bitterlich, Courteney Tunstead, Andrew E Hogan, James A Ankrum, Karen English.
      Innate training of macrophages can be beneficial for the clearance of pathogens. However, for certain chronic conditions, innate training can have detrimental effects due to an excessive production of pro-inflammatory cytokines. Obesity is a condition that is associated with a range of increased pro-inflammatory training stimuli including the free fatty acid palmitate. Mesenchymal stromal cells (MSCs) are powerful immunomodulators and known to suppress inflammatory macrophages via a range of soluble factors. We show that palmitate training of murine bone-marrow-derived macrophages and human monocyte-derived macrophages (MDMs) results in an increased production of TNFα and IL-6 upon stimulation with lipopolysaccharide and is associated with epigenetic remodeling. Palmitate training led to metabolic changes, however, MSCs did not alter the metabolic profile of human MDMs. Using a transwell system, we demonstrated that human bone marrow MSCs block palmitate training in both murine and human macrophages suggesting the involvement of secreted factors. MSC disruption of the training process occurs through more than one pathway. Suppression of palmitate-enhanced TNFα production is associated with cyclooxygenase-2 activity in MSCs, while secretion of interleukin-1 receptor antagonist by MSCs is required to suppress palmitate-enhanced IL-6 production in MDMs.
    Keywords:  innate training; macrophages; mesenchymal stromal cells; obesity; palmitate
    DOI:  https://doi.org/10.1016/j.jcyt.2024.10.011
  9. Int J Mol Sci. 2024 Nov 14. pii: 12223. [Epub ahead of print]25(22):
    Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
    Jing Wang, Yuanli He, Feiming Hu, Chenchen Hu, Yuanjie Sun, Kun Yang, Shuya Yang.
      Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.
    Keywords:  immune cells; immunotherapy; metabolic reprogramming; the tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms252212223
  10. Cell Death Dis. 2024 Nov 26. 15(11): 859
    Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications.
    Yongxin Zheng, Junlu Sun, Zhiting Luo, Yimin Li, Yongbo Huang.
      Regulated cell death (RCD) refers to the form of cell death that can be regulated by various biomacromolecules. Each cell death modalities have their distinct morphological changes and molecular mechanisms. However, intense evidences suggest that lipid peroxidation can be the common feature that initiates and propagates the cell death. Excessive lipid peroxidation alters the property of membrane and further damage the proteins and nucleic acids, which is implicated in various human pathologies. Here, we firstly review the classical chain process of lipid peroxidation, and further clarify the current understanding of the myriad roles and molecular mechanisms of lipid peroxidation in various RCD types. We also discuss how lipid peroxidation involves in diseases and how such intimate association between lipid peroxidation-driven cell death and diseases can be leveraged to develop rational therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-024-07244-x
  11. Pathogens. 2024 Nov 15. pii: 1005. [Epub ahead of print]13(11):
    The Intriguing Connection Between the Gut and Lung Microbiomes.
    Magdalena Druszczynska, Beata Sadowska, Jakub Kulesza, Nikodem Gąsienica-Gliwa, Ewelina Kulesza, Marek Fol.
      Recent advances in microbiome research have uncovered a dynamic and complex connection between the gut and lungs, known as the gut-lung axis. This bidirectional communication network plays a critical role in modulating immune responses and maintaining respiratory health. Mediated by immune interactions, metabolic byproducts, and microbial communities in both organs, this axis demonstrates how gut-derived signals, such as metabolites and immune modulators, can reach the lung tissue via systemic circulation, influencing respiratory function and disease susceptibility. To explore the implications of this connection, we conducted a systematic review of studies published between 2001 and 2024 (with as much as nearly 60% covering the period 2020-2024), using keywords such as "gut-lung axis", "microbiome", "respiratory disease", and "immune signaling". Studies were selected based on their relevance to gut-lung communication mechanisms, the impact of dysbiosis, and the role of the gut microbiota in respiratory diseases. This review provides a comprehensive overview of the gut-lung microbiome axis, emphasizing its importance in regulating inflammatory and immune responses linked to respiratory health. Understanding this intricate pathway opens new avenues for microbiota-targeted therapeutic strategies, which could offer promising interventions for respiratory diseases like asthma, chronic obstructive pulmonary disease, and even infections. The insights gained through this research underscore the potential of the gut-lung axis as a novel target for preventative and therapeutic approaches in respiratory medicine, with implications for enhancing both gut and lung health.
    Keywords:  gut–lung axis; microbiome; respiratory diseases
    DOI:  https://doi.org/10.3390/pathogens13111005
  12. Commun Med (Lond). 2024 Nov 23. 4(1): 246
    Early nasal microbiota and subsequent respiratory tract infections in infants with cystic fibrosis.
    SCILD study group
       BACKGROUND: Respiratory tract infections (RTIs) drive lung function decline in children with cystic fibrosis (CF). While the respiratory microbiota is clearly associated with RTI pathogenesis in infants without CF, data on infants with CF is scarce. We compared nasal microbiota development between infants with CF and controls and assessed associations between early-life nasal microbiota, RTIs, and antibiotic treatment in infants with CF.
    METHODS: We included 50 infants with CF and 30 controls from two prospective birth cohorts followed throughout the first year of life. We collected 1511 biweekly nasal swabs and analyzed the microbiota after amplifying the V3-V4 region of the 16S rRNA gene. We conducted structured weekly interviews to assess respiratory symptoms and antibiotic treatment. We calculated generalized additive mixed models and permutational analysis of variance.
    RESULTS: Here, we show that the nasal microbiota is already altered before the first RTI or antibiotic treatment in infants with CF. Microbiota diversity differs between infants with CF and controls following RTIs and/or antibiotic treatment. CF infants with lower α-diversity have a higher number of subsequent RTIs.
    CONCLUSIONS: Early nasal microbiota alterations may reflect predisposition or predispose to RTIs in infants with CF, and further change after RTIs and antibiotic treatment. This highlights the potential of targeting the nasal microbiota in CF-related RTI management, while also questioning current practices in the era of novel modulator therapies.
    DOI:  https://doi.org/10.1038/s43856-024-00616-6
  13. J Exp Med. 2025 Jan 06. pii: e20232055. [Epub ahead of print]222(1):
    Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.
    Tasia D Kellogg, Simona Ceglia, Benedikt M Mortzfeld, Tanvi M Tanna, Abigail L Zeamer, Matthew R Mancini, Sage E Foley, Doyle V Ward, Shakti K Bhattarai, Beth A McCormick, Andrea Reboldi, Vanni Bucci.
      The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production-deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile-induced morbidity and mortality. This effect is nullified in Pou2f3-/- mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.
    DOI:  https://doi.org/10.1084/jem.20232055
  14. bioRxiv. 2024 Apr 30. pii: 2024.04.30.591719. [Epub ahead of print]
    Toll-Like-Receptor 5 protects against pulmonary fibrosis by reducing lung dysbiosis.
    Yosuke Sakamachi, Emma Wiley, Alma Solis, Collin G Johnson, Xianglin Meng, Salik Hussain, Jay H Lipinski, David N O'Dwyer, Thomas Randall, Jason Malphurs, Brian Papas, Benjamin G Wu, Yonghua Li, Matthias Kugler, Sanya Mehta, Carol S Trempus, Seddon Y Thomas, Jian-Liang Li, Lecong Zhou, Peer W Karmaus, Michael B Fessler, John A McGrath, Kevin Gibson, Daniel J Kass, Anatoli Gleiberman, Avram Walts, Rachele Invernizzi, Phil L Molyneaux, Ivana V Yang, Yingze Zhang, Naftali Kaminski, Leopoldo N Segal, David A Schwartz, Andrei V Gudkov, Stavros Garantziotis.
      Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation. IPF results from maladaptive responses to lung epithelial injury, but the underlying mechanisms remain unclear. Here, we show that deficiency in the innate immune receptor, toll-like receptor 5 (TLR5), is associated with IPF in humans and with increased susceptibility to epithelial injury and experimental fibrosis in mice, while activation of lung epithelial TLR5 through a synthetic flagellin analogue protects from experimental fibrosis. Mechanistically, epithelial TLR5 activation induces antimicrobial gene expression and ameliorates dysbiosis after lung injury. In contrast, TLR5 deficiency in mice and IPF patients is associated with lung dysbiosis. Elimination of the microbiome in mice through antibiotics abolishes the protective effect of TLR5 and reconstitution of the microbiome rescues the observed phenotype. In aggregate, TLR5 deficiency is associated with IPF and dysbiosis in humans and in the murine model of pulmonary fibrosis. Furthermore, TLR5 protects against pulmonary fibrosis in mice and this protection is mediated by effects on the microbiome.
    One-sentence summary: Deficiency in the innate immune receptor TLR5 is a risk factor for pulmonary fibrosis, because TLR5 prevents microbial dysbiosis after lung injury.
    DOI:  https://doi.org/10.1101/2024.04.30.591719
  15. Front Immunol. 2024 ;15 1469163
    Branched-chain amino acid catabolism promotes M2 macrophage polarization.
    Manxi Lu, Da Luo, Zixuan Zhang, Feng Ouyang, Yihong Shi, Changyong Hu, Hang Su, Yining Li, Jiayi Zhang, Qian Gui, Tian-Shu Yang.
       Introduction: During an immune response, macrophages undergo systematic metabolic rewiring tailored to support their functions. Branched-chain amino acid (BCAA) metabolism has been reported to modulate macrophage function; however, its role in macrophage alternative activation remain unclear. We aimed to investigate the role of BCAA metabolism in macrophage alternative activation.
    Method: The metabolomics of BMDM-derived M0 and M2 macrophages were analyzed using LC-MS. BCAAs were supplemented and genes involved in BCAA catabolism were inhibited during M2 macrophage polarization. The expression of M2 marker genes was assessed through RT-qPCR, immunofluorescence, and flow cytometry.
    Results and discussion: Metabolomic analysis identified increased BCAA metabolism as one of the most significantly rewired pathways upon alternative activation. M2 macrophages had significantly lower BCAA levels compared to controls. BCAA supplementation promoted M2 macrophage polarization both in vitro and in vivo and increased oxidative phosphorylation in M2 macrophages. Blocking BCAA entry into mitochondria by knockdown of SLC25A44 inhibited M2 macrophage polarization. Furthermore, M2 macrophages polarization was suppressed by knockdown of Branched-chain amino-acid transaminase 2 (BCAT2) and branched chain keto acid dehydrogenase E1 subunit alpha (BCKDHA), both of which are key enzymes involved in BCAA oxidation. Overall, our findings suggest that BCAA catabolism plays an important role in polarization toward M2 macrophages.
    Keywords:  BCAA; BCAT2; BCKDHA; M2 macrophages; SLC25A44
    DOI:  https://doi.org/10.3389/fimmu.2024.1469163
  16. Semin Immunol. 2024 Nov 26. pii: S1044-5323(24)00051-4. [Epub ahead of print]76 101913
    The tissue glycome as regulator of immune activation and tolerance mediated by C-type lectins and Siglecs.
    Eleonora Nardini, Ernesto Rodriguez, Yvette van Kooyk.
      The immune system is a complex network of highly specialized microenvironments, denominated niches, which arise from dynamic interactions between immune and parenchymal cells as well as acellular components such as structural elements and local molecular signals. A critical, yet underexplored, layer shaping these niches is the glycome, the complete repertoire of glycans and glycoconjugates produced by cells. The glycome is prevalent in the outer membrane of cells and their secreted components, and can be sensed by glycan binding receptors on immune cells. These receptors detect changes in glycosylation and consequently modulate immune cell activity, trafficking, and signalling, altering homeostasis. Tissues like the brain and the placenta are prone to accommodate tolerance, while the gut and the thymus are sensitive to inflammation. We provide here an overview of current literature that shows the impact of altered glycosylation of tissues on host immune cells and how interference in this process may lead to new diagnostics and immune therapeutics, aiming to restore the immune balance in autoimmunity and cancer.
    Keywords:  Autoimmunity; Cancer; DC-SIGN; Glycans; Immune response; Siglecs; Tissue-glycome
    DOI:  https://doi.org/10.1016/j.smim.2024.101913
  17. Physiol Res. 2024 Nov 29. 73(S2): S557
    Influence of Hypoxia on the Airway Epithelium.
    K Procházková, J Uhlík.
      The necessity of oxygen for metabolic processes means that hypoxia can lead to serious cell and tissue damage. On the other hand, in some situations, hypoxia occurs under physiological conditions and serves as an important regulation factor. The airway epithelium is specific in that it gains oxygen not only from the blood supply but also directly from the luminal air. Many respiratory diseases are associated with airway obstruction or excessive mucus production thus leading to luminal hypoxia. The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction. Keywords: Secretory cells, Motile cilia, Epithelial barrier, Oxygenation, Obstructive respiratory diseases.
  18. Cell Death Dis. 2024 Nov 29. 15(11): 864
    Ezrin drives adaptation of monocytes to the inflamed lung microenvironment.
    Ravindra Gudneppanavar, Caterina Di Pietro, Hasan H Öz, Ping-Xia Zhang, Ee-Chun Cheng, Pamela H Huang, Toma Tebaldi, Giulia Biancon, Stephanie Halene, Adam D Hoppe, Catherine Kim, Anjelica L Gonzalez, Diane S Krause, Marie E Egan, Neetu Gupta, Thomas S Murray, Emanuela M Bruscia.
      Ezrin, an actin-binding protein, orchestrates the organization of the cortical cytoskeleton and plasma membrane during cell migration, adhesion, and proliferation. Its role in monocytes/macrophages (MΦs) is less understood. Here, we used a monocyte/MΦ-specific ezrin knock-out mouse model to investigate the contribution of ezrin to monocyte recruitment and adaptation to the lung extracellular matrix (ECM) in response to lipopolysaccharide (LPS). Our study revealed that LPS induces ezrin expression in monocytes/MΦs and is essential for monocytes to adhere to lung ECM, proliferate, and differentiate into tissue-resident interstitial MΦs. Mechanistically, the loss of ezrin in monocytes disrupts activation of focal adhesion kinase and AKT serine-threonine protein kinase signaling, essential for lung-recruited monocytes and monocyte-derived MΦs to adhere to the ECM, proliferate, and survive. In summary, our data show that ezrin plays a role beyond structural cellular support, influencing diverse monocytes/MΦ processes and signaling pathways during inflammation, facilitating their differentiation into tissue-resident macrophages.
    DOI:  https://doi.org/10.1038/s41419-024-07255-8
  19. Nat Commun. 2024 Nov 28. 15(1): 10329
    Adaptation in human immune cells residing in tissues at the frontline of infections.
    Irepan Salvador-Martínez, Jesus Murga-Moreno, Juan C Nieto, Clara Alsinet, David Enard, Holger Heyn.
      Human immune cells are under constant evolutionary pressure, primarily through their role as first line of defence against pathogens. Most studies on immune adaptation are, however, based on protein-coding genes without considering their cellular context. Here, using data from the Human Cell Atlas, we infer the gene adaptation rate of the human immune landscape at cellular resolution. We find abundant cell types, like progenitor cells during development and adult cells in barrier tissues, to harbour significantly increased adaptation rates. We confirm the adaptation of tissue-resident T and NK cells in the adult lung located in compartments directly facing external challenges, such as respiratory pathogens. Analysing human iPSC-derived macrophages responding to various challenges, we find adaptation in early immune responses. Together, our study suggests host benefits to control pathogen spread at early stages of infection, providing a retrospect of forces that shaped the complexity, architecture, and function of the human body.
    DOI:  https://doi.org/10.1038/s41467-024-54603-5
  20. Biomolecules. 2024 Nov 17. pii: 1457. [Epub ahead of print]14(11):
    Modulation of the Gut-Lung Axis by Water Kefir and Kefiran and Their Impact on Toll-like Receptor 3-Mediated Respiratory Immunity.
    Stefania Dentice Maidana, Julio Nicolás Argañaraz Aybar, Leonardo Albarracin, Yoshiya Imamura, Luciano Arellano-Arriagada, Fu Namai, Yoshihito Suda, Keita Nishiyama, Julio Villena, Haruki Kitazawa.
      The beneficial effect of milk kefir on respiratory heath has been previously demonstrated; however, water kefir and kefiran in the context of respiratory viral infections have not been investigated. Water kefir and kefiran could be alternatives to milk kefir for their application in persons with lactose intolerance or milk allergy and could be incorporated into vegan diets. Using mice models, this work demonstrated that the oral administration of water kefir or kefiran can modulate the respiratory Toll-like receptor (TLR3)-mediated innate antiviral immunity and improve the resistance to respiratory syncytial virus (RSV) infection. The treatment of mice with water kefir or kefiran for 6 days improved the production of interferons (IFN-β and IFN-γ) and antiviral factors (Mx2, OAS1, RNAseL, and IFITM3) in the respiratory tract after the activation of the TLR3 signaling pathway, differentially modulated the balance of pro- and anti-inflammatory cytokines, reduced RSV replication, and diminished lung tissue damage. Maintaining a proper balance between anti-inflammatory and pro-inflammatory mediators is vital for ensuring an effective and safe antiviral immune response, and the results of this work show that water kefir and kefiran would help to maintain that balance promoting a controlled inflammatory response that defends against infection while minimizing tissue damage.
    Keywords:  TLR3; antiviral immunity; gut–lung axis; probiotics; respiratory immunity; water kefir
    DOI:  https://doi.org/10.3390/biom14111457
  21. Nat Commun. 2024 Nov 30. 15(1): 10424
    Approaches to investigate tissue-resident innate lymphocytes metabolism at the single-cell level.
    Carrie Corkish, Cristhiane Favero Aguiar, David K Finlay.
      Tissue-resident innate immune cells have important functions in both homeostasis and pathological states. Despite advances in the field, analyzing the metabolism of tissue-resident innate lymphocytes is still challenging. The small number of tissue-resident innate lymphocytes such as ILC, NK, iNKT and γδ T cells poses additional obstacles in their metabolic studies. In this review, we summarize the current understanding of innate lymphocyte metabolism and discuss potential pitfalls associated with the current methodology relying predominantly on in vitro cultured cells or bulk-level comparison. Meanwhile, we also summarize and advocate for the development and adoption of single-cell metabolic assays to accurately profile the metabolism of tissue-resident immune cells directly ex vivo.
    DOI:  https://doi.org/10.1038/s41467-024-54516-3
  22. J Invest Dermatol. 2024 Nov 22. pii: S0022-202X(24)02956-7. [Epub ahead of print]
    Fibroblast-mediated macrophage recruitment supports acute wound healing.
    Veronica M Amuso, MaryEllen R Haas, Paula O Cooper, Ranojoy Chatterjee, Sana Hafiz, Shatha Salameh, Chiraag Gohel, Miguel F Mazumder, Violet Josephson, Sarah S Kleb, Khatereh Khorsandi, Anelia Horvath, Ali Rahnavard, Brett A Shook.
      Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single nuclei RNA-sequencing, we defined changes in gene expression associated with inflammation at 1-day post-wounding (dpw) in mouse skin. Compared to keratinocytes and myeloid cells, we detected enriched expression of pro-inflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL33 compared to SCA1- fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound bed macrophages and monocytes during injury-induced inflammation with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.
    Keywords:  CCL2; fibroblast; macrophage; single nuclei RNA-sequencing; wound healing
    DOI:  https://doi.org/10.1016/j.jid.2024.10.609
  23. Trends Endocrinol Metab. 2024 Nov 27. pii: S1043-2760(24)00294-7. [Epub ahead of print]
    Host metabolic inflammation fueled by bacterial DNA.
    Ke Wang, Karina Cunha E Rocha, Houji Qin, Zixuan Zeng, Wei Ying.
      Metabolic diseases, characterized by chronic low-grade inflammation, exhibit a compromised gut barrier allowing the translocation of bacteria-derived products to bloodstream and distant metabolic organs. Bacterial DNA can be detected in metabolic tissues during the onset of these diseases, highlighting its role in the development of metabolic diseases. Extracellular vesicles (EVs) are involved in the delivery of bacterial DNA to the local tissues, and its sensing by the host triggers local and system inflammation. Understanding bacterial DNA translocation and its induced inflammation is crucial in deciphering metabolic disease pathways. Here, we delve into the mechanisms dictating the interaction between host physiology and bacterial DNA, focusing on its origin and delivery, host immune responses against it, and its roles in metabolic disorders.
    Keywords:  bacterial DNA; complement immunity; extracellular vesicles; immune response; metabolic diseases; tissue inflammation
    DOI:  https://doi.org/10.1016/j.tem.2024.11.003
  24. J Inflamm Res. 2024 ;17 9071-9085
    Interleukin 1β Mediates the Pathogenesis of Nasal Mucosal Epithelial Barrier Dysfunction in Allergic Rhinitis.
    Hanrui Wang, Xiaoyu Song, Yao Wang, Ting Yang, Wanchen Liu, Yakui Mou, Chao Ren, Xicheng Song.
       Background: The nasal mucosal epithelial barrier is the primary site of allergic rhinitis (AR). Interleukin-1β (IL-1β), as a crucial factor in immune inflammation, not only plays a crucial role in hypersensitivity reactions but also affects the digestive mucosa and skin epithelial barrier. However, the role of IL-1β in the nasal mucosal epithelial barrier in AR has not been reported, and this study aimed to investigate the effect and possible mechanisms involved.
    Methods: Dermatophagoides pteronyssinus 1 was used as an allergen to construct an AR mouse model and stimulate human nasal mucosal epithelial cells (HNEpCs) and observe the expression changes of IL-1β and epithelial barrier indicators CLDN1 and OCLN in mouse nasal mucosa and HNEpCs. Then, the possible mechanisms of action were explored via exogenous IL-1β stimulation and pharmacological inhibition of IL-1β or its receptor interleukin-1 receptor type 1 (IL-1R1).
    Results: The results showed that Dermatophagoides pteronyssinus 1-primed mouse nasal mucosa or human HENpCs had increased expression of IL-1β and decreased CLDN1 and OCLN, and IL-1β could directly lead to reduced expression of epithelial barrier indexes in HNEpCs. In addition, inhibition of IL-1β or IL-1R1 can effectively alleviate the damage to the epithelial barrier.
    Conclusion: IL-1β has a destructive effect on the nasal mucosal epithelial barrier in AR, and inhibition of IL-1β or its receptor IL-1R1 can effectively protect the nasal mucosal barrier. IL-1β is a potential target for the treatment of AR.
    Keywords:  DerP1; allergic rhinitis; epithelial barrier; interleukin-1β; nasal mucous membrane
    DOI:  https://doi.org/10.2147/JIR.S488340
  25. Nat Microbiol. 2024 Dec;9(12): 3097-3109
    A framework for understanding collective microbiome metabolism.
    Matthias Huelsmann, Olga T Schubert, Martin Ackermann.
      Microbiome metabolism underlies numerous vital ecosystem functions. Individual microbiome members often perform partial catabolism of substrates or do not express all of the metabolic functions required for growth. Microbiome members can complement each other by exchanging metabolic intermediates and cellular building blocks to achieve a collective metabolism. We currently lack a mechanistic framework to explain why microbiome members adopt partial metabolism and how metabolic functions are distributed among them. Here we argue that natural selection for proteome efficiency-that is, performing essential metabolic fluxes at a minimal protein investment-explains partial metabolism of microbiome members, which underpins the collective metabolism of microbiomes. Using the carbon cycle as an example, we discuss motifs of collective metabolism, the conditions under which these motifs increase the proteome efficiency of individuals and the metabolic interactions they result in. In summary, we propose a mechanistic framework for how collective metabolic functions emerge from selection on individuals.
    DOI:  https://doi.org/10.1038/s41564-024-01850-3
  26. Int J Mol Sci. 2024 Nov 10. pii: 12078. [Epub ahead of print]25(22):
    Unraveling Macrophage Polarization: Functions, Mechanisms, and "Double-Edged Sword" Roles in Host Antiviral Immune Responses.
    Meng Yao, Meilin Li, Dingkun Peng, Yijing Wang, Su Li, Ding Zhang, Bo Yang, Hua-Ji Qiu, Lian-Feng Li.
      Numerous viruses that propagate through the respiratory tract may be initially engulfed by macrophages (Mφs) within the alveoli, where they complete their first replication cycle and subsequently infect the adjacent epithelial cells. This process can lead to significant pathological damage to tissues and organs, leading to various diseases. As essential components in host antiviral immune systems, Mφs can be polarized into pro-inflammatory M1 Mφs or anti-inflammatory M2 Mφs, a process involving multiple signaling pathways and molecular mechanisms that yield diverse phenotypic and functional features in response to various stimuli. In general, when infected by a virus, M1 macrophages secrete pro-inflammatory cytokines to play an antiviral role, while M2 macrophages play an anti-inflammatory role to promote the replication of the virus. However, recent studies have shown that some viruses may exhibit the opposite trend. Viruses have evolved various strategies to disrupt Mφ polarization for efficient replication and transmission. Notably, various factors, such as mechanical softness, the altered pH value of the endolysosomal system, and the homeostasis between M1/M2 Mφs populations, contribute to crucial events in the viral replication cycle. Here, we summarize the regulation of Mφ polarization, virus-induced alterations in Mφ polarization, and the antiviral mechanisms associated with these changes. Collectively, this review provides insights into recent advances regarding Mφ polarization in host antiviral immune responses, which will contribute to the development of precise prevention strategies as well as management approaches to disease incidence and transmission.
    Keywords:  antiviral immunity; immune escape; macrophage polarization; macrophages; viruses
    DOI:  https://doi.org/10.3390/ijms252212078
  27. Nat Rev Immunol. 2024 Nov 29.
    Sialylated IgG restrains lung inflammation.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-024-01120-7
  28. Biochim Biophys Acta Gen Subj. 2024 Nov 22. pii: S0304-4165(24)00174-0. [Epub ahead of print]1869(1): 130731
    Extracellular matrix stiffness facilitates neurite outgrowth by reprogramming the fatty acid oxidation-dependent macrophage polarization.
    Shan Wang, Xu Chu, Zhaoyang Liu, Congwei Wang, Zhongyu Fan, Yazhou Chen, Zhengguo Zhang.
      The extracellular matrix (ECM) is involved in various of pathophysiology processes, such as wound healing and neurogenesis. During tissue injury, the recruited bone marrow-derived monocytes in the impaired site undergo functional and phenotypic changes and participate in the initiation, maintenance, and resolution phases of tissue repair. However, the effects of ECM stiffness on monocyte differentiation and function remain largely unknown. Herein, we developed a gelatin-hydroxyphenylpropionic acid-based hydrogel with different substrate stiffnesses by varying hydrogen peroxide concentrations, which demonstrated good biocompatibility. Furthermore, the high substrate stiffness hydrogel could polarize macrophage into immunosuppressive phenotype with increased expression of interleukin 10, transforming growth factor β, CD206, and CD163. Twenty three differentially expressed metabolites were identified in stiff hydrogel-cultured macrophages in comparison with soft hydrogel cultured macrophages via metabolite analysis. In addition, 4-hydroxybenzoic acid was the most upregulated metabolite, which could confer protection against neuronal and acute inflammation. Mechanistically, the high substrate stiffness induced macrophage immunosuppressive differentiation by upregulating the expression of the fatty acid oxidation (FAO)-related proteins peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-δ. Consistently, the FAO inhibitor etomoxir reversed the high substrate stiffness mediated macrophage immunosuppressive polarization and neurite outgrowth. Therefore, the alteration in macrophage phenotype induced by increased substrate stiffness can promote tissue repair in clinical applications.
    Keywords:  Extracellular matrix stiffness; Hydrogels; Macrophages; Metabolism; Wound healing
    DOI:  https://doi.org/10.1016/j.bbagen.2024.130731
  29. Clin Exp Med. 2024 Nov 28. 25(1): 12
    The bacterial microbiome and cancer: development, diagnosis, treatment, and future directions.
    Hasnaa H Qasem, Wael M El-Sayed.
      The term "microbiome" refers to the collection of bacterial species that reside in the human body's tissues. Sometimes, it is used to refer to all microbial entities (bacteria, viruses, fungi, and others) which colonize the human body. It is now generally acknowledged that the microbiome plays a critical role in the host's physiological processes and general well-being. Changes in the structure and/or function of the microbiome (dysbiosis) are linked to the development of many diseases including cancer. The claim that because of their negatively charged membrane, cancer cells are more vulnerable to some bacteria than normal cells and that is how the link between these bacteria and cancer evolved has been refuted. Furthermore, the relationship between the microbiome and cancer is more evident in the emerging field of cancer immunotherapy. In this narrative review, we detailed the correlation between the presence/absence of specific bacterial species and the development, diagnosis, prognosis, and treatment of some types of cancer including colorectal, lung, breast, and prostate cancer. In addition, we discussed the mechanisms of microbiome-cancer interactions including genotoxin production, the role of free radicals, modification of signaling pathways in host cells, immune modulation, and modulation of drug metabolism by microbiome. Future directions and clinical application of microbiome in the early detection, prognosis, and treatment of cancer emphasizing on the role of fecal transplantation, probiotics, prebiotics, and microbiome biomarkers were also considered.
    Keywords:  Dysbiosis; Fecal transplantation; Genotoxin; Immune modulation; Inflammation; Oxidative stress; Prebiotics; Probiotics
    DOI:  https://doi.org/10.1007/s10238-024-01523-9
  30. Biomolecules. 2024 Nov 18. pii: 1461. [Epub ahead of print]14(11):
    Plasmalogens in Innate Immune Cells: From Arachidonate Signaling to Ferroptosis.
    Jesús Balsinde, María A Balboa.
      Polyunsaturated fatty acids such as arachidonic acid are indispensable components of innate immune signaling. Plasmalogens are glycerophospholipids with a vinyl ether bond in the sn-1 position of the glycerol backbone instead of the more common sn-1 ester bond present in "classical" glycerophospholipids. This kind of phospholipid is particularly rich in polyunsaturated fatty acids, especially arachidonic acid. In addition to or independently of the role of plasmalogens as major providers of free arachidonic acid for eicosanoid synthesis, plasmalogens also perform a varied number of functions. Membrane plasmalogen levels may determine parameters of the plasma membrane, such as fluidity and the formation of microdomains that are necessary for efficient signal transduction leading to optimal phagocytosis by macrophages. Also, plasmalogens may be instrumental for the execution of ferroptosis. This is a nonapoptotic form of cell death that is associated with oxidative stress. This review discusses recent data suggesting that, beyond their involvement in the cellular metabolism of arachidonic acid, the cells maintain stable pools of plasmalogens rich in polyunsaturated fatty acids for executing specific responses.
    Keywords:  arachidonic acid; ferroptosis; inflammation; innate immunity; plasmalogens; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/biom14111461
  31. Life Sci. 2024 Nov 26. pii: S0024-3205(24)00869-5. [Epub ahead of print]360 123279
    Recent advances in crosstalk between immune cells and cancer cells with ferroptosis.
    Jinfeng Yi, Wanting Zhang, Yingpu Li, He Ren, Yuhang Xiang, Cong Qiao.
      Ferroptosis, a regulated form of cell death distinct from apoptosis and necrosis. Key hallmarks include iron-dependent lipid peroxidation, glutathione depletion, and intracellular iron accumulation, all of which are counteracted by specific cellular defenses. However, the immunosuppressive effects of ferroptosis induction in cancer immunotherapy remain unresolved. This review summarizes the recent advancements in ferroptosis research, focusing on its defensive mechanisms. It analyzes how ferroptosis affects both cancer and immune cells, highlighting its potential inhibitory effects on anti-tumor immunity and possible promotion of pro-tumor immune responses. Finally, this review briefly introduces case studies that combined ferroptosis induction with immunotherapy, offering novel perspectives for cancer treatment.
    Keywords:  Cancer cell; Ferroptosis; Immune cell; Immunotherapy
    DOI:  https://doi.org/10.1016/j.lfs.2024.123279
  32. Biomedicines. 2024 Oct 22. pii: 2417. [Epub ahead of print]12(11):
    Microbiota Orchestra in Parkinson's Disease: The Nasal and Oral Maestros.
    Nádia Rei, Miguel Grunho, José João Mendes, Jorge Fonseca.
      Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons, leading to a range of motor and non-motor symptoms.
    BACKGROUND/OBJECTIVES: Over the past decade, studies have identified a potential link between the microbiome and PD pathophysiology. The literature suggests that specific bacterial communities from the gut, oral, and nasal microbiota may be involved in neuroinflammatory processes, which are hallmarks of PD. This review aims to comprehensively analyze the current research on the composition, diversity, and dysbiosis characteristics of the nasal and oral microbiota in PD.
    METHODS: Through a comprehensive search across scientific databases, we identify twenty original studies investigating the nasal and oral microbiota in PD.
    RESULTS: Most of these studies demonstrate the substantial roles of bacterial communities in neuroinflammatory pathways associated with PD progression. They also underscore the influences of microbiota-derived factors on key aspects of PD pathology, including alpha-synuclein aggregation and immune dysregulation.
    CONCLUSIONS: Finally, we discuss the potential diagnostic and therapeutic implications of modulating the nasal and oral microbiota in PD management. This analysis seeks to identify potential avenues for future research in order to clarify the complex relationships between these microorganisms and PD.
    Keywords:  Parkinson’s disease; dysbiosis; microbiome; nasal microbiota; oral microbiota
    DOI:  https://doi.org/10.3390/biomedicines12112417
  33. Inflamm Regen. 2024 Nov 27. 44(1): 49
    Cell fusion dynamics: mechanisms of multinucleation in osteoclasts and macrophages.
    Hideaki Sabe, Yasuhito Yahara, Masaru Ishii.
      Cell-cell fusion is a vital biological process where the membranes of two or more cells merge to form a syncytium. This phenomenon is critical in various physiological and pathological contexts, including embryonic development, tissue repair, immune responses, and the progression of several diseases. Osteoclasts, which are cells from the monocyte/macrophage lineage responsible for bone resorption, have enhanced functionality due to cell fusion. Additionally, other multinucleated giant cells (MGCs) also arise from the fusion of monocytes and macrophages, typically during chronic inflammation and reactions to foreign materials such as prostheses or medical devices. Foreign body giant cells (FBGCs) and Langhans giant cells (LGCs) emerge only under pathological conditions and are involved in phagocytosis, antigen presentation, and the secretion of inflammatory mediators. This review provides a comprehensive overview of the mechanisms underlying the formation of multinucleated cells, with a particular emphasis on macrophages and osteoclasts. Elucidating the intracellular structures, signaling cascades, and fusion-mediating proteins involved in cell-cell fusion enhances our understanding of this fundamental biological process and helps identify potential therapeutic targets for disorders mediated by cell fusion.
    Keywords:  Cell fusion; Macrophages; Multinucleated giant cells; Multinucleation; Osteoclasts
    DOI:  https://doi.org/10.1186/s41232-024-00360-3
  34. Int J Biochem Cell Biol. 2024 Nov 24. pii: S1357-2725(24)00196-1. [Epub ahead of print] 106703
    Immune-Epithelial Cell Interactions in Lung Development, Homeostasis and Disease.
    Masahiro Yoshida, Romina Arzili, Marko Z Nikolić.
      The importance of the crosstalk between lung epithelial and immune cells, which emerges from early development and lasts throughout life, is corroborated by a growing body of scientific evidence. This communication not only has a role in driving lung morphogenesis during development, but it is also required in adulthood for the maintenance of homeostasis and repair following infection or injury. Disruption of the intricate immune-epithelial crosstalk can lead to diseases such as COPD and IPF. In this review we summarise the current knowledge regarding the communication between various immune and epithelial cells in development, homeostasis, regeneration and disease, while identifying the current gaps in our knowledge required to facilitate the development of more effective therapies.
    Keywords:  Epithelium; Immune development; Immune-epithelial crosstalk; Lung epithelial development; Lung homeostasis and repair
    DOI:  https://doi.org/10.1016/j.biocel.2024.106703
  35. Nat Microbiol. 2024 Dec;9(12): 3079-3080
    A year of microbiology.
      
    DOI:  https://doi.org/10.1038/s41564-024-01880-x
  36. Exp Hematol. 2024 Nov 22. pii: S0301-472X(24)00550-2. [Epub ahead of print] 104685
    "Microbiome and Hemato-immune Aging".
    Alban Johansson, Nicole Pui-Yu Ho, Hitoshi Takizawa.
      Microbiome is a highly complex and diverse symbiotic component that undergoes dynamic changes with the organismal aging. Microbial perturbations, termed dysbiosis, exert strong influence on dysregulating the bone marrow niche and subsequently promoting the aging of hematopoietic and immune system. Besides, accumulating studies have revealed the substantial impact of intestinal microbiome on the initiation and progression of age-related hematologic alteration and diseases, such as clonal hematopoiesis and blood cancers. Current therapeutic approaches to restore the altered microbiome diversity target specific pathobionts and are demonstrated to improve clinical outcomes of anti-hematologic malignancy treatments. In this review, we discuss the interplay between the microbiome and the hemato-immune system during aging process. We also shed light on the emerging therapeutic strategies to tackle the dysbiosis for amelioration of aging and disease progression.
    DOI:  https://doi.org/10.1016/j.exphem.2024.104685
  37. bioRxiv. 2024 Nov 16. pii: 2024.11.16.623925. [Epub ahead of print]
    Intraspecific Diversity of Staphylococcus aureus Populations Isolated from Cystic Fibrosis Respiratory Infections.
    Ashley M Alexander, Hui Qi Loo, Lauren Askew, Vishnu Raghuram, Timothy D Read, Joanna B Goldberg.
      Chronic bacterial infections are often polymicrobial, comprising multiple bacterial species or variants of the same species. Because chronic infections may last for decades, they have the potential to generate high levels of intraspecific variation through within-host diversification over time, and the potential for superinfections to occur through the introduction of multiple pathogen populations to the ongoing infection. Traditional methods for identifying infective agents generally involve isolating one single colony from a given sample, usually after selecting for a specific pathogen or antibiotic resistance profile. Isolating a recognized virulent or difficult to treat pathogen is an important part of informing clinical treatment and correlative research; however, these reductive methods alone, do not provide researchers or healthcare providers with the potentially important perspective on the true pathogen population structure and dynamics over time. To begin to address this limitation, in this study, we compare findings on Staphylococcus aureus single colonies versus and pools of colonies taken from fresh sputum samples from three patients with cystic fibrosis to isolates collected from the same sputum samples and processed by the clinical microbiology laboratory. Phenotypic and genotypic analysis of isolated S. aureus populations revealed coexisting lineages in two of three sputum samples as well as population structures that were not reflected in the single colony isolates. Altogether, our observations presented here demonstrate that clinically relevant diversity can be missed with standard sampling methods when assessing chronic infections. More broadly, this work outlines the potential impact that comprehensive population-level sampling may have for both research efforts and more effective treatment practices.
    Data Summary: The authors confirm all supporting data, code and protocols have been provided within the article.
    DOI:  https://doi.org/10.1101/2024.11.16.623925
  38. bioRxiv. 2024 Nov 13. pii: 2024.11.12.622464. [Epub ahead of print]
    Resource landscape shapes the composition and stability of the human vaginal microbiota.
    Tsukushi Kamiya, Mircea T Sofonea, Michael France, Nicolas Tessandier, Ignacio G Bravo, Carmen Lia Murall, Jacques Ravel, Samuel Alizon.
      The vaginal microbiota has demonstrated associations with women's and newborns' health. Despite its comparatively simple composition relative to other human microbiota systems, the ecological processes that underpin the dynamics and stability of vaginal microbial communities remain mechanistically elusive. A crucial, yet so far under-explored, aspect of vaginal microbiota ecology is the role played by nutritional resources. Glycogen and its derivatives, produced by vaginal epithelia, are accessible to all bacterial constituents of the microbiota. Concurrently, free sialic acid and fucose offer supplementary nutritional resources for bacterial strains capable of cleaving them from glycans, which are structurally integral to mucus. Notably, bacteria adept at sialic acid exploitation are often correlated with adverse clinical outcomes and are frequently implicated in bacterial vaginosis (BV). In this study, we introduce a novel mathematical model tailored to human vaginal microbiota dynamics to explore the interactions between bacteria and their respective nutritional landscapes. Our resource-based model examines the impact of the relative availability of glycogen derivatives (accessible to all bacterial species) and sialic acid (exclusive to some BV-associated bacteria) on the composition of the vaginal microbiota. Our findings elucidate that the prevalence of BV-associated bacteria is intricately linked to their exclusive access to specific nutritional resources. This private access fortifies communities dominated by BV-associated bacteria, rendering them resilient to compositional transitions. We provide empirical support for our model's predictions from longitudinal microbiota composition and metabolomic data, collected from a North American cohort. The insights gleaned from this study shed light on potential pathways for BV prevention.
    DOI:  https://doi.org/10.1101/2024.11.12.622464
  39. Int J Biol Macromol. 2024 Nov 22. pii: S0141-8130(24)08802-0. [Epub ahead of print] 137991
    Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming.
    Jia-Wen Xie, Yin-Feng Guo, Shu-Hao Fan, Ying Zheng, Hui-Lin Zhang, Yan Zhang, Yi Zhang, Li-Rong Lin.
      Syphilis is a sexually transmitted disease caused by Treponema pallidum. The mechanisms enabling T. pallidum to persist despite macrophage eradication efforts in syphilis remain unclear. Pathogens can exploit senescent cells to enhance host susceptibility, and cellular senescence can be induced by pyroptosis, which known as inflammatory senescence. While recent studies have linked metabolic reprogramming to inflammatory senescence, their role in syphilis remained to be clarified. This study investigated the mechanisms of Tp47 on metabolic reprogramming and inflammatory senescence in macrophages. The results demonstrated that Tp47 triggered NLRP3 inflammasome-mediated pyroptosis by activating the phosphorylation of EIF2AK2 (a protein kinase), increasing senescence-associated pro-inflammatory cytokines secretion and leading to inflammatory senescence in macrophages. Additionally, Tp47 competitively bound to pyruvate kinase M2 (PKM2) with STUB1(a ubiquitin ligase), thereby inhibiting PKM2 ubiquitination degradation. By promoting the Y105 phosphorylation of PKM2, Tp47 modulated the intracellular function of PKM2, and facilitated PKM2-mediated metabolic reprogramming, which produced lactate that subsequently led to EIF2AK2 phosphorylation. Furthermore, inhibitors targeting EIF2AK2, lactate, glycolysis, and PKM2 effectively suppressed the inflammatory senescence induced by Tp47. In conclusion, Tp47 could mediate immune metabolic reprogramming through interaction with PKM2 to trigger macrophage inflammatory senescence. These discoveries offer a novel perspective for targeted therapies against syphilis.
    Keywords:  Inflammatory senescence; Metabolic reprogramming; Syphilis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137991
  40. Int J Mol Sci. 2024 Nov 17. pii: 12337. [Epub ahead of print]25(22):
    The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease.
    Zheng Wang, Robert C Kaplan, Robert D Burk, Qibin Qi.
      Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Recent advancements in high-throughput omics techniques have enhanced our understanding of the human microbiome's role in the development of CVDs. Although the relationship between the gut microbiome and CVDs has attracted considerable research attention and has been rapidly evolving in recent years, the role of the oral microbiome remains less understood, with most prior studies focusing on periodontitis-related pathogens. In this review, we summarized previously reported associations between the oral microbiome and CVD, highlighting known CVD-associated taxa such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We also discussed the interactions between the oral and gut microbes. The potential mechanisms by which the oral microbiota can influence CVD development include oral and systemic inflammation, immune responses, cytokine release, translocation of oral bacteria into the bloodstream, and the impact of microbial-related products such as microbial metabolites (e.g., short-chain fatty acids [SCFAs], trimethylamine oxide [TMAO], hydrogen sulfide [H2S], nitric oxide [NO]) and specific toxins (e.g., lipopolysaccharide [LPS], leukotoxin [LtxA]). The processes driven by these mechanisms may contribute to atherosclerosis, endothelial dysfunction, and other cardiovascular pathologies. Integrated multi-omics methodologies, along with large-scale longitudinal population studies and intervention studies, will facilitate a deeper understanding of the metabolic and functional roles of the oral microbiome in cardiovascular health. This fundamental knowledge will support the development of targeted interventions and effective therapies to prevent or reduce the progression from cardiovascular risk to clinical CVD events.
    Keywords:  cardiovascular diseases; gut microbiome; inflammatory markers; microbial metabolites; oral microbiome
    DOI:  https://doi.org/10.3390/ijms252212337
  41. Antiviral Res. 2024 Nov 22. pii: S0166-3542(24)00252-3. [Epub ahead of print]232 106041
    Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation.
    Md Ruhul Amin, Khandaker N Anwar, M J Ashraf, Mahmood Ghassemi, Richard M Novak.
      Influenza A viruses (IAVs) and endemic coronaviruses (eCoVs) are common etiologic agents for seasonal respiratory infections. The human H1N1 of IAV and coronavirus OC43 (HCoV-OC43) can result in hospitalization, acute respiratory distress syndrome (ARDS), and even death, particularly in immunocompromised individuals. They infect the epithelium of the respiratory tract by interacting with host cell sialic acid (Sia)- linked receptors whose synthesis is catalyzed by sialyltransferases (STs). Viral coinfection is challenging to treat because of the need to target specific components of two or more distinct pathogens. Emerging drug and vaccine resistance due to the high mutation rate of viral genomes further complicates the treatment and prevention of viral infection. Sialylation mediated by STs may be a potential drug target for treating viral diseases. ST is an attractive target because it could be effective before identifying the pathogen that has occurred, providing a novel direction for overcoming drug resistance and achieving a broad-spectrum antiviral effect. We developed an H1N1 and OC43 mono or coinfection model using 14 days post-plating (14 PP) human primary small airway epithelial cells (HSAEC) grown on transwell inserts at an air-fluid interface (ALI), mimicking in vivo cellular dynamics. Using this model, we have observed that mono or coinfection with OC43 and H1N1 results in increased sialic acid levels and synergistic viral infection. We showed for the first time that H1N1 and OC43 mono- and coinfection in HSAEC caused increased expression and activity of STs, which can be blocked by pan-STs inhibitor (3Fax-Peracetyl Neu5Ac) with no host cell toxicity.
    Keywords:  H1N1; HCoV-OC43; HSAEC; STs and STs inhibitor
    DOI:  https://doi.org/10.1016/j.antiviral.2024.106041
  42. Nestle Nutr Inst Workshop Ser. 2024 ;100 139-149
    What Does Healthy Microbiome Development Look Like? State of the Art and Beyond.
    Giles Major, Shaillay Kumar Dogra, Norbert Sprenger.
      The community of microorganisms colonizing the gut changes during the first postnatal years of life. This ecosystem, henceforth described as the microbiome, modulates infant physiology and health, but uncertainty remains about the significance of variation in microbiome composition and function. Some may be tolerable, yet some microbiomes may be less healthy than others. Most efforts to identify parameters of microbiome health focus on adults, and derived concepts may not directly translate to early life that is characterized by dynamic and sequential changes. Data suggest that an orderly progression from an immature neonatal microbiome to a mature adult state is preferable to delayed or over-rapid development. This can be parameterized as a "microbiome development trajectory". Diet modifies early life microbiome development and is the principal modifiable factor to this end. Infants fed with infant formulas show different microbiome development trajectories from breastfed infants. Early data suggest that formulas containing a specific blend of human milk oligosaccharides partially mitigate this difference. Introduction of a complementary diet complexifies the identification of diet-microbiome development interactions. A better understanding will only be achievable through detailed, longitudinal characterization of large cohorts.
    DOI:  https://doi.org/10.1159/000540144
  43. Nature. 2024 Nov 27.
    Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.
    Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz I Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P Böttcher, Sakari Vanharanta, Anna C Obenauf.
      The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3-7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3-5,8-10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide-major histocompatibility complex class I complexes from tumour cells through 'cross-dressing'. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08257-4
  44. Trends Immunol. 2024 Nov 26. pii: S1471-4906(24)00274-6. [Epub ahead of print]
    Breaking down IgA: Tomasiella immunophila enlightens microbiome-immune interactions.
    Duncan B Sutherland, Lucia M Kato, Sidonia Fagarasan.
      The recent discovery by Lu and colleagues of Tomasiella immunophila, a bacterium that degrades IgA, offers insights into microbial influences on mucosal immunity and evolutionary immune trade-offs. By modulating IgA titers, T. immunophila influences the dynamic interactions and balance between the host and pathogen. This has implications for immune health, microbiome research, and therapeutics.
    DOI:  https://doi.org/10.1016/j.it.2024.11.003
  45. Nature. 2024 Nov 27.
    Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
    Yun Liao, Iris H Gao, Takato Kusakabe, Woan-Yu Lin, Alexander Grier, Xiangyu Pan, Olga Morzhanaeva, Terrance P Shea, Hiroshi Yano, Danielle Karo-Atar, Kaitlin A Olsen, Ji Hoon Oh, Kurt J Vandegrift, Irah L King, Christina A Cuomo, David Artis, Barbara Rehermann, Neil Lipman, Iliyan D Iliev.
      The gut mycobiota is crucial for intestinal homeostasis and immune function1. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism2,3. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome. Kazachstania pintolopesii colonization occurs in a bacteria-independent manner, results in enhanced colonization resistance to other fungi and is shielded from host immune surveillance, allowing commensal presence. Following changes in the mucosal environment, K. pintolopesii colonization triggers a type 2 immune response in mice and induces gastrointestinal eosinophilia. Mechanistically, we determined that K. pintolopesii activates type 2 immunity via the induction of epithelial IL-33 and downstream IL-33-ST2 signalling during mucus fluctuations. Kazachstania pintolopesii-induced type 2 immunity enhanced resistance to helminth infections or aggravated gastrointestinal allergy in a context-dependent manner. Our findings indicate that K. pintolopesii is a mouse commensal and serves as a valuable model organism for studying gut fungal commensalism and immunity in its native host. Its unnoticed presence in mouse facilities highlights the need to evaluate its influence on experimental outcomes and phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08213-2
  46. J Clin Invest. 2024 Nov 14. pii: e183331. [Epub ahead of print]
    Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote colonization.
    Yiwei Dai, Vonetta L Edwards, Qian Yu, Hervé Tettelin, Daniel C Stein, Wenxia Song.
      Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women's cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of Opa isoforms that bind the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, decreased GC-induced IL-10 secretion. These results show that GC induce local secretion of IL-10, a potent anti-inflammatory cytokine, at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding, providing a potential mechanism for GC asymptomatic colonization in women.
    Keywords:  Bacterial infections; Cytokines; Infectious disease
    DOI:  https://doi.org/10.1172/JCI183331
  47. Biology (Basel). 2024 Nov 15. pii: 931. [Epub ahead of print]13(11):
    Transcriptional Responses of Lacticaseibacillus rhamnosus to TNFα, IL-6, IL-8, and IL-10 Cytokines.
    Ksenia M Klimina, Marina S Dyachkova, Vladimir A Veselovsky, Natalia V Zakharevich, Aleksandra A Strokach, Oksana V Selezneva, Egor A Shitikov, Dmitry A Bespiatykh, Roman A Yunes, Elena U Poluektova, Maya V Odorskaya, Polina S Ostroukhova, Sergey A Bruskin, Valeriy N Danilenko, Evgenii I Olekhnovich.
      The interaction between gut microbiota and the host immune system is a complex and understudied field, with cytokines like TNFα, IL-6, IL-8, and IL-10 playing pivotal roles. Commensal bacteria, including lactobacilli, respond to these cytokines through adaptive mechanisms that support their survival and function within the gut. While the influence of cytokines on pathogenic bacteria is well documented, their impact on commensal bacteria, particularly lactobacilli, remains underexplored. This study investigates the transcriptional responses of Lacticaseibacillus rhamnosus strains K32 and R19-3 to various cytokines using next-generation RNA sequencing (RNA-seq). Our findings reveal that cytokines, especially IL-8 and IL-10, significantly alter the L. rhamnosus transcriptome, affecting genes involved in carbohydrate metabolism, stress response, and transcriptional regulation. Notably, IL-8 and IL-10 induce a significant downregulation of genes related to the phosphotransferase system, suggesting a reduction in metabolic activity in response to inflammatory signals. This study unveils a previously unexplored aspect of L. rhamnosus adaptation, highlighting its intricate response to cytokine signals. By modulating gene expression, L. rhamnosus may mitigate the adverse effects of inflammation and promote gut health. These insights could inform the development of targeted probiotic therapies for inflammatory bowel disease (IBD) and other conditions with altered cytokine levels. Our results suggest that co-evolution between a host and gut microbiota enables bacteria to respond to specific cytokines through gene expression changes, revealing a unique and underexplored facet of the interaction between commensal bacteria and the host organism.
    Keywords:  RNA sequencing; commensal gut microbiota; cytokine signaling; host immune system response; immunomodulatory bacteria; phosphotransferase system; phylogenetic profiling; transcriptome
    DOI:  https://doi.org/10.3390/biology13110931
  48. J Transl Autoimmun. 2024 Dec;9 100257
    The interplay between epidermal barrier distribution, microbiota composition, and immune infiltrate defines and stratifies psoriasis patients and is associated with disease severity.
    Elizabeth M Ortega Rocha, Paul Hernández-Herrera, Sofia V de Los Santos-Carmona, Saraí G De León-Rodríguez, Ángel Juárez-Flores, Vadim Pérez-Koldenkova, Octavio Castro-Escamilla, Samira Muñoz-Cruz, Alicia Lemini-López, Laura C Bonifaz.
      Psoriasis is a chronic inflammatory autoimmune skin disease characterized by keratinocyte hyperproliferation, primarily driven by the IL-23/IL-17 axis. In addition to immune response, various skin components, including the epidermal barrier and the skin microbiota, have been individually implicated in the disease pathogenesis. Here, we aimed to investigate the interplay between epidermal tight junctions, Staphylococcus aureus enterotoxin B (SEB), and CD4 T cell-mediated immune responses. By immunofluorescence analyses of skin biopsies, we observed that claudin-1 distribution was significantly altered in psoriatic patients, which correlated with the localization of Staphylococcus aureus and SEB across skin layers and with disease severity. Furthermore, functional CD4 TCRvβ17 cells were associated with SEB presence in patients skin and positively correlated with psoriasis severity. Notably, in patients with SEB detected in the dermis, CD4 TCRvβ17 IL-17 cells were linked to barrier abnormalities. Unsupervised analysis stratified psoriasis patients into three groups based on SEB presence and location, supporting the previous findings. The patient group with SEB in the dermis exhibited improved responses to biological therapy, including reductions in PASI score, claudin-1 fragmentation, S. aureus and SEB presence, and CD4 TCRvβ17 cell percentages. Our findings emphasize the complex interplay between epidermal barrier distribution, SEB localization, and functional CD4 TCRvβ17 cells in psoriatic skin, highlighting their potential in patient stratification in association with the severity of the disease.
    Keywords:  Epidermal barrier; Psoriasis; Psoriasis severity; Skin microbiota
    DOI:  https://doi.org/10.1016/j.jtauto.2024.100257
  49. Front Immunol. 2024 ;15 1469696
    Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells.
    Ali Hazrati, Seyed Mohamad Javad Mirarefin, Kosar Malekpour, Arezou Rahimi, Arezou Khosrojerdi, Ashkan Rasouli, Susan Akrami, Sara Soudi.
      Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.
    Keywords:  exosomes; immune cells; immunomodulation; inflammation; mesenchymal stem cells; pulmonary disease
    DOI:  https://doi.org/10.3389/fimmu.2024.1469696
  50. Biomolecules. 2024 Nov 13. pii: 1443. [Epub ahead of print]14(11):
    Ferroptosis in Cancer: Epigenetic Control and Therapeutic Opportunities.
    Roberta Veglia Tranchese, Sabrina Battista, Laura Cerchia, Monica Fedele.
      Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathway in cancer biology. This review delves into the epigenetic mechanisms that modulate ferroptosis in cancer cells, focusing on how DNA methylation, histone modifications, and non-coding RNAs influence the expression and function of essential genes involved in this process. By unraveling the complex interplay between these epigenetic mechanisms and ferroptosis, the article sheds light on novel gene targets and functional insights that could pave the way for innovative cancer treatments to enhance therapeutic efficacy and overcome resistance in cancer therapy.
    Keywords:  cancer therapy; epigenetic regulation; ferroptosis; lipid peroxidation; therapeutic targets
    DOI:  https://doi.org/10.3390/biom14111443
  51. Cell Host Microbe. 2024 Nov 21. pii: S1931-3128(24)00409-8. [Epub ahead of print]
    Protection against Clostridioides difficile disease by a naturally avirulent strain.
    Qiwen Dong, Stephen Harper, Emma McSpadden, Sophie S Son, Marie-Maude Allen, Huaiying Lin, Rita C Smith, Carolyn Metcalfe, Victoria Burgo, Che Woodson, Anitha Sundararajan, Amber Rose, Mary McMillin, David Moran, Jessica Little, Michael W Mullowney, Ashley M Sidebottom, Louis-Charles Fortier, Aimee Shen, Eric G Pamer.
      Clostridioides difficile is a leading cause of healthcare infections. Gut dysbiosis promotes C. difficile infection (CDI) and CDIs promote gut dysbiosis, leading to frequent CDI recurrence. Although therapies preventing recurrent CDI have been developed, including live biotherapeutic products, existing therapies are costly and do not prevent primary infections. Here, we show that an avirulent C. difficile isolate, ST1-75, protects mice from developing colitis induced by a virulent R20291 strain when coinfected at a 1:1 ratio. In metabolic analyses, avirulent ST1-75 depletes amino acids more rapidly than virulent R20291 and supplementation with amino acids ablates this competitive advantage, indicating that ST1-75 limits the growth of virulent R20291 through amino acid depletion. Overall, our study identifies inter-strain nutrient depletion as a potentially exploitable mechanism to reduce the incidence of CDI and reveals that the ST1-75 strain may be a biotherapeutic agent that can prevent CDI in high-risk patients.
    Keywords:  C. difficile; Stickland fermentation; amino acids; colitis; intraspecies competition; mouse model; virulence
    DOI:  https://doi.org/10.1016/j.chom.2024.11.003
  52. Sheng Wu Gong Cheng Xue Bao. 2024 Nov 25. 40(11): 3888-3901
    [Advancements in the regulatory effects and mechanisms of the immune metabolite itaconate in diseases].
    Zhongkun Cheng, Jingxian Zhao, Yanyan Liu, Ling Xu, Guangwei Zhao, Xingwei Ni, Xiaowei Yang.
      Itaconate is a pivotal intermediate metabolite in the tricarboxylic acid (TCA) cycle of immune cells. It is produced by decarboxylation of cis-aconitic acid under the catalysis of aconitate decarboxylase 1 (ACOD1), which is encoded by the immune response gene 1 (IRG1). Itaconate has become a focal point of research on immunometabolism. Studies have demonstrated that itaconate plays a crucial role in diseases by regulating inflammation, remodeling cell metabolism, and participating in epigenetic regulation. This paper reviewed the research progress in itaconnate from its chemical structure, regulatory effects on different diseases, and mechanisms, proposes the future research directions, aiming to provide a theoretical basis for the development of itaconate-related drugs.
    Keywords:  cell metabolism; genetic regulation; immunization; inflammation; itaconate; metabolites
    DOI:  https://doi.org/10.13345/j.cjb.240328
  53. Int J Mol Sci. 2024 Nov 17. pii: 12345. [Epub ahead of print]25(22):
    Diversity of Neurotransmitter-Producing Human Skin Commensals.
    Samane Rahmdel, Moushumi Purkayastha, Mulugeta Nega, Elisa Liberini, Ningna Li, Arif Luqman, Holger Brüggemann, Friedrich Götz.
      Recent findings indicate that human microbiota can excrete trace amines, dopamine, and serotonin. These neurotransmitters (NTs) can either affect classical neurotransmitter signaling or directly trigger trace amine-associated receptors (TAARs), with still unclear consequences for host physiology. Compared to gut microbiota, less information is available on the role of skin microbiota in NT production. To explore this, 1909 skin isolates, mainly from the genera Staphylococcus, Bacillus, and Corynebacterium, were tested for NT production. Only 6.7% of the isolates were capable of producing NTs, all of which belonged to the Staphylococcus genus. Based on substrate specificity, we identified two distinct profiles among the NT producers. One group primarily produced tryptamine (TRY) and phenylethylamine (PEA), while the other mainly produced tyramine (TYM) and dopamine (Dopa). These differing production profiles could be attributed to the activity of two distinct aromatic amino acid decarboxylase enzymes, SadA and TDC, responsible for generating the TRY/PEA and TYM/Dopa product spectra, respectively. SadA and TDC orthologues differ in structure and size; SadA has approximately 475 amino acids, whereas the TDC type consists of about 620 amino acids. The genomic localization of the respective genes also varies: tdc genes are typically found in small, conserved gene clusters, while sadA genes are not. The heterologous expression of sadA and tdc in Escherichia coli yielded the same product spectrum as the parent strains. The possible effects of skin microbiota-derived NTs on neuroreceptor signaling in the human host remain to be investigated.
    Keywords:  aromatic amino acid decarboxylase; microbiota; neurotransmitter; skin; trace amines
    DOI:  https://doi.org/10.3390/ijms252212345
  54. Mucosal Immunol. 2024 Nov 22. pii: S1933-0219(24)00113-2. [Epub ahead of print]
    IgA facilitates the persistence of the mucosal pathogen Helicobacter pylori.
    Mariela Artola-Borán, Lydia Kirsche, Angela Fallegger, Peter Leary, Mine Tanriover, Tanja Goodwin, Gavin Geiger, Siegfried Hapfelmeier, Shida Yousefi, Hans-Uwe Simon, Isabelle C Arnold, Anne Müller.
      IgA antibodies have an important role in clearing mucosal pathogens. In this study, we have examined the contribution of IgA to the immune control of the gastrointestinal bacterial pathogens Helicobacter pylori and Citrobacter rodentium. Both bacteria trigger a strong local IgA response that results in bacterial IgA coating in mice and in gastritis patients. Class switching to IgA depends on Peyer's patches, T-cells, eosinophils, and eosinophil-derived TGF-β in both models. In the case of H. pylori, IgA secretion and bacterial coating also depend on a functional bacterial type IV secretion system, which drives the generation of Th17 cells and the IL-17-dependent expression of the polymeric immunoglobulin receptor PIGR. IgA-/- mice are hypercolonized with C. rodentium in all examined tissues, suffer from more severe weight loss and develop more colitis. In contrast, H. pylori is controlled more efficiently in IgA-/- mice than their WT counterparts. The effects of IgA deficiency of the offspring can be compensated by maternal IgA delivered by WT foster mothers. We attribute the improved immune control observed in IgA-/- mice to IgA-mediated protection from complement killing, as H. pylori colonization is restored to wild type levels in a composite strain lacking both IgA and the central complement component C3. IgA antibodies can thus have protective or detrimental activities depending on the infectious agent.
    Keywords:  GI tract infections; Immunoglobulin class switching; Immunopathology; Innate immune defense; Mucosal immunity
    DOI:  https://doi.org/10.1016/j.mucimm.2024.11.006
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