bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒04‒07
thirty-one papers selected by
Chun-Chi Chang, University Hospital Zurich

  1. Curr Res Immunol. 2024 ;5 100077
      Macrophages restrain microbial infection and reinstate tissue homeostasis. The mitochondria govern macrophage metabolism and serve as pivot in innate immunity, thus acting as immunometabolic regulon. Metabolic pathways produce electron flows that end up in mitochondrial electron transport chain (mtETC), made of super-complexes regulating multitude of molecular and biochemical processes. Cell-intrinsic and extrinsic factors influence mtETC structure and function, impacting several aspects of macrophage immunity. These factors provide the macrophages with alternate fuel sources and metabolites, critical to gain functional competence and overcoming pathogenic stress. Mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS) generated through the mtETC are important innate immune attributes, which help macrophages in mounting antibacterial responses. Recent studies have demonstrated the role of mtETC in governing mitochondrial dynamics and macrophage polarization (M1/M2). M1 macrophages are important for containing bacterial pathogens and M2 macrophages promote tissue repair and wound healing. Thus, mitochondrial bioenergetics and metabolism are intimately coupled with innate immunity. In this review, we have addressed mtETC function as innate rheostats that regulate macrophage reprogramming and innate immune responses. Advancement in this field encourages further exploration and provides potential novel macrophage-based therapeutic targets to control unsolicited inflammation.
    Keywords:  Bacterial infection; Innate immunity; M1-M2 macrophages; Super-complex; mtETC; mtROS
  2. Immunol Rev. 2024 Apr 02.
      Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self-renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage-committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self-renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise.
    Keywords:   Mycobacterium tuberculosis ; BCG; HSC metabolism; adaptive immunity; evolutionary immunology; hematopoiesis; hematopoietic stem cells; innate immune memory; interferon pathways; interleukin‐1; trained immunity; β‐glucan
  3. Front Immunol. 2024 ;15 1330461
      Macrophages are highly plastic cells ubiquitous in various tissues, where they perform diverse functions. They participate in the response to pathogen invasion and inflammation resolution following the immune response, as well as the maintenance of homeostasis and proper tissue functions. Macrophages are generally considered long-lived cells with relatively strong resistance to numerous cytotoxic factors. On the other hand, their death seems to be one of the principal mechanisms by which macrophages perform their physiological functions or can contribute to the development of certain diseases. In this review, we scrutinize three distinct pro-inflammatory programmed cell death pathways - pyroptosis, necroptosis, and ferroptosis - occurring in macrophages under specific circumstances, and explain how these cells appear to undergo dynamic yet not always final changes before ultimately dying. We achieve that by examining the interconnectivity of these cell death types, which in macrophages seem to create a coordinated and flexible system responding to the microenvironment. Finally, we discuss the complexity and consequences of pyroptotic, necroptotic, and ferroptotic pathway induction in macrophages under two pathological conditions - atherosclerosis and cancer. We summarize damage-associated molecular patterns (DAMPs) along with other microenvironmental factors, macrophage polarization states, associated mechanisms as well as general outcomes, as such a comprehensive look at these correlations may point out the proper methodologies and potential therapeutic approaches.
    Keywords:  atherosclerosis; cancer; cell death; ferroptosis; macrophages; necroptosis; pyroptosis; tumor-associated macrophages
  4. J Med Microbiol. 2024 Apr;73(4):
      Introduction.Staphylococcus aureus is the leading cause of acute medical implant infections, representing a significant modern medical concern. The success of S. aureus as a pathogen in these cases resides in its arsenal of virulence factors, resistance to multiple antimicrobials, mechanisms of immune modulation, and ability to rapidly form biofilms associated with implant surfaces. S. aureus device-associated, biofilm-mediated infections are often persistent and notoriously difficult to treat, skewing innate immune responses to promote chronic reoccurring infections. While relatively little is known of the role neutrophils play in response to acute S. aureus biofilm infections, these effector cells must be efficiently recruited to sites of infection via directed chemotaxis. Here we investigate the effects of modulating CXC chemokine receptor 2 (CXCR2) activity, predominantly expressed on neutrophils, during S. aureus implant-associated infection.Hypothesis. We hypothesize that modulation of CXCR2 expression and/or signalling activities during S. aureus infection, and thus neutrophil recruitment, extravasation and antimicrobial activity, will affect infection control and bacterial burdens in a mouse model of implant-associated infection.Aim. This investigation aims to elucidate the impact of altered CXCR2 activity during S. aureus biofilm-mediated infection that may help develop a framework for an effective novel strategy to prevent morbidity and mortality associated with implant infections.Methodology. To examine the role of CXCR2 during S. aureus implant infection, we employed a mouse model of indwelling subcutaneous catheter infection using a community-associated methicillin-resistant S. aureus (MRSA) strain. To assess the role of CXCR2 induction or inhibition during infection, treatment groups received daily intraperitoneal doses of either Lipocalin-2 (Lcn2) or AZD5069, respectively. At the end of the study, catheters and surrounding soft tissues were analysed for bacterial burdens and dissemination, and Cxcr2 transcription within the implant-associated tissues was quantified.Results. Mice treated with Lcn2 developed higher bacterial burdens within the soft tissue surrounding the implant site, which was associated with increased Cxcr2 expression. AZD5069 treatment also resulted in increased implant- and tissues-associated bacterial titres, as well as enhanced Cxcr2 expression.Conclusion. Our results demonstrate that CXCR2 plays an essential role in regulating the severity of S. aureus implant-associated infections. Interestingly, however, perturbation of CXCR2 expression or signalling both resulted in enhanced Cxcr2 transcription and elevated implant-associated bacterial burdens. Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of S. aureus biofilm-mediated infection.
    Keywords:  CXCR2; Staphylococcus aureus; biofilm; neutrophil
  5. bioRxiv. 2024 Mar 18. pii: 2023.05.11.539887. [Epub ahead of print]
      The nasal mucosa is frequently the initial site of respiratory viral infection, replication, and transmission. Recent work has started to clarify the independent responses of epithelial, myeloid, and lymphoid cells to viral infection in the nasal mucosa, but their spatiotemporal coordination and relative contributions remain unclear. Furthermore, understanding whether and how primary infection shapes tissue-scale memory responses to secondary challenge is critical for the rational design of nasal-targeting therapeutics and vaccines. Here, we generated a single-cell RNA-sequencing (scRNA-seq) atlas of the murine nasal mucosa sampling three distinct regions before and during primary and secondary influenza infection. Primary infection was largely restricted to respiratory mucosa and induced stepwise changes in cell type, subset, and state composition over time. Type I Interferon (IFN)-responsive neutrophils appeared 2 days post infection (dpi) and preceded transient IFN-responsive/cycling epithelial cell responses 5 dpi, which coincided with broader antiviral monocyte and NK cell accumulation. By 8 dpi, monocyte-derived macrophages (MDMs) expressing Cxcl9 and Cxcl16 arose alongside effector cytotoxic CD8 and Ifng -expressing CD4 T cells. Following viral clearance (14 dpi), rare, previously undescribed K rt13+ n asal i mmune- i nteracting f loor e pithelial (KNIIFE) cells expressing multiple genes with immune communication potential increased concurrently with tissue-resident memory T (TRM)-like cells and early IgG+/IgA+ plasmablasts. Proportionality analysis coupled with cell-cell communication inference, alongside validation by in situ microscopy, underscored the CXCL16-CXCR6 signaling axis between MDMs and effector CD8 T cells 8dpi and KNIIFE cells and TRM cells 14 dpi. Secondary influenza challenge with a homologous or heterologous strain administered 60 dpi induced an accelerated and coordinated myeloid and lymphoid response without epithelial proliferation, illustrating how tissue-scale memory to natural infection engages both myeloid and lymphoid cells to reduce epithelial regenerative burden. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses upon rechallenge.
  6. Cell Rep. 2024 Apr 01. pii: S2211-1247(24)00350-4. [Epub ahead of print]43(4): 114022
      Staphylococcus aureus causes the majority of skin and soft tissue infections, but this pathogen only transiently colonizes healthy skin. However, this transient skin exposure enables S. aureus to transition to infection. The initial adhesion of S. aureus to skin corneocytes is mediated by surface protein G (SasG). Here, phylogenetic analyses reveal the presence of two major divergent SasG alleles in S. aureus: SasG-I and SasG-II. Structural analyses of SasG-II identify a nonaromatic arginine in the binding pocket of the lectin subdomain that mediates adhesion to corneocytes. Atomic force microscopy and corneocyte adhesion assays indicate that SasG-II can bind to a broader variety of ligands than SasG-I. Glycosidase treatment results in different binding profiles between SasG-I and SasG-II on skin cells. In addition, SasG-mediated adhesion is recapitulated using differentiated N/TERT keratinocytes. Our findings indicate that SasG-II has evolved to adhere to multiple ligands, conferring a distinct advantage to S. aureus during skin colonization.
    Keywords:  Aap; CP: Microbiology; SasG; Staphylococcus epidermidis; Staphylococcusaureus; corneocytes; keratinocytes; skin
  7. Trends Immunol. 2024 Apr 04. pii: S1471-4906(24)00032-2. [Epub ahead of print]
      Macrophages are vital tissue components involved in organogenesis, maintaining homeostasis, and responses to disease. Mouse models have significantly improved our understanding of macrophages. Further investigations into the characteristics and development of human macrophages are crucial, considering the substantial anatomical and physiological distinctions between mice and humans. Despite challenges in human macrophage research, recent studies are shedding light on the ontogeny and function of human macrophages. In this opinion, we propose combinations of cutting-edge approaches to examine the diversity, development, niche, and function of human tissue-resident macrophages. These methodologies can facilitate our exploration of human macrophages more efficiently, ideally providing new therapeutic avenues for macrophage-relevant disorders.
    Keywords:  hematopoiesis; human macrophage; human organoids; macrophage development; single-cell technologies; tissue-resident macrophage
  8. Cell Metab. 2024 Apr 02. pii: S1550-4131(24)00086-X. [Epub ahead of print]36(4): 684-701
      One of the key modes of microbial metabolism occurring in the gut microbiome is fermentation. This energy-yielding process transforms common macromolecules like polysaccharides and amino acids into a wide variety of chemicals, many of which are relevant to microbe-microbe and microbe-host interactions. Analogous transformations occur during the production of fermented foods, resulting in an abundance of bioactive metabolites. In foods, the products of fermentation can influence food safety and preservation, nutrient availability, and palatability and, once consumed, may impact immune and metabolic status, disease expression, and severity. Human signaling pathways perceive and respond to many of the currently known fermented food metabolites, though expansive chemical novelty remains to be defined. Here we discuss several aspects of fermented food-associated microbes and metabolites, including a condensed history, current understanding of their interactions with hosts and host-resident microbes, connections with commercial probiotics, and opportunities for future research on human health and disease and food sustainability.
    Keywords:  fermentation; fermented foods; gut microbiome; metabolomics; microbial metabolites
  9. Biochem Pharmacol. 2024 Mar 30. pii: S0006-2952(24)00170-9. [Epub ahead of print] 116187
      Metabolic reprogramming underlies the etiology and pathophysiology of respiratory diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). The dysregulated cellular activities driving airway inflammation and remodelling in these diseases have reportedly been linked to aberrant shifts in energy-producing metabolic pathways: glycolysis and oxidative phosphorylation (OXPHOS). The rewiring of glycolysis and OXPHOS accompanying the therapeutic effects of many clinical compounds and natural products in asthma, IPF, and COPD, supports targeting metabolism as a therapeutic approach for respiratory diseases. Correspondingly, inhibiting glycolysis has largely attested effective against experimental asthma, IPF, and COPD. However, modulating OXPHOS and its supporting catabolic pathways like mitochondrial pyruvate catabolism, fatty acid β-oxidation (FAO), and glutaminolysis for these respiratory diseases remain inconclusive. An emerging repertoire of metabolic enzymes are also interconnected to these canonical metabolic pathways that similarly possess therapeutic potential for respiratory diseases. Taken together, this review highlights the urgent demand for future studies to ascertain the role of OXPHOS in different respiratory diseases, under different stimulatory conditions, and in different cell types. While this review provides strong experimental evidence in support of the inhibition of glycolysis for asthma, IPF, and COPD, further verification by clinical trials is definitely required.
    Keywords:  Asthma; Chronic obstructive pulmonary disease; Glycolysis; Idiopathic pulmonary fibrosis; Oxidative phosphorylation
  10. Curr Opin Virol. 2024 Apr 01. pii: S1879-6257(24)00023-3. [Epub ahead of print]66 101409
      Influenza A virus (IAV) infections pose a global health challenge that necessitates a comprehensive understanding of the host immune response to devise effective therapeutic interventions. As monocytes and macrophages play crucial roles in host defence, inflammation, and repair, this review explores the intricate journey of these cells during and after IAV infection. First, we highlight the dynamics and functions of lung-resident macrophage populations post-IAV. Second, we review the current knowledge of recruited monocytes and monocyte-derived cells, emphasising their roles in viral clearance, inflammation, immunomodulation, and tissue repair. Third, we shed light on the consequences of IAV-induced macrophage alterations on long-term lung immunity. We conclude by underscoring current knowledge gaps and exciting prospects for future research in unravelling the complexities of macrophage responses to respiratory viral infections.
  11. Res Sq. 2024 Mar 21. pii: [Epub ahead of print]
      Polymicrobial infection of the airways is a hallmark of obstructive lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary disease. Pulmonary exacerbations (PEx) in these conditions are associated with accelerated lung function decline and higher mortality rates. An understanding of the microbial underpinnings of PEx is challenged by high inter-patient variability in airway microbial community profiles. We analyzed bacterial communities in 880 CF sputum samples and developed microbiome descriptors to model community reorganization prior to and during 18 PEx. We identified two microbial dysbiosis regimes with opposing ecology and dynamics. Pathogen-governed PEx showed hierarchical community reorganization and reduced diversity, whereas anaerobic bloom PEx displayed stochasticity and increased diversity. A simulation of antimicrobial treatment predicted better efficacy for hierarchically organized communities. This link between PEx type, microbiome organization, and treatment success advances the development of personalized clinical management in CF and, potentially, other obstructive lung diseases.
  12. Eur J Immunol. 2024 Mar 31. e2350631
      The intestinal barrier is mainly formed by a monolayer of epithelial cells, which forms a physical barrier to protect the gut tissues from external insults and provides a microenvironment for commensal bacteria to colonize while ensuring immune tolerance. Moreover, various immune cells are known to significantly contribute to intestinal barrier function by either directly interacting with epithelial cells or by producing immune mediators. Fulfilling this function of the gut barrier for mucosal homeostasis requires not only the intrinsic regulation of intestinal epithelial cells (IECs) but also constant communication with immune cells and gut microbes. The reciprocal interactions between IECs and immune cells modulate mucosal barrier integrity. Dysregulation of barrier function could lead to dysbiosis, inflammation, and tumorigenesis. In this overview, we provide an update on the characteristics and functions of IECs, and how they integrate their functions with tissue immune cells and gut microbiota to establish gut homeostasis.
    Keywords:  Epithelial cells; Intestinal immunity; Mucosal immunity
  13. Immunol Rev. 2024 Apr 03.
      Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, and tolerance regulate similar "signature" inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK-STAT signaling and interferon-stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin-mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-γ-mediated priming, affects regulation of AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a "training-priming continuum" model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.
    Keywords:  chromatin; epigenetics; innate immune training; interferon; monocytes; priming
  14. Discov Immunol. 2023 ;2(1): kyad008
      Monocytes are circulating myeloid cells that are derived from dedicated progenitors in the bone marrow. Originally thought of as mere precursors for the replacement of tissue macrophages, it is increasingly clear that monocytes execute distinct effector functions and may give rise to monocyte-derived cells with unique properties from tissue-resident macrophages. Recently, the advent of novel experimental approaches such as single-cell analysis and fate-mapping tools has uncovered an astonishing display of monocyte plasticity and heterogeneity, which we believe has emerged as a key theme in the field of monocyte biology in the last decade. Monocyte heterogeneity is now recognized to develop as early as the progenitor stage through specific imprinting mechanisms, giving rise to specialized effector cells in the tissue. At the same time, monocytes must overcome their susceptibility towards cellular death to persist as monocyte-derived cells in the tissues. Environmental signals that preserve their heterogenic phenotypes and govern their eventual fates remain incompletely understood. In this review, we will summarize recent advances on the developmental trajectory of monocytes and discuss emerging concepts that contributes to the burgeoning field of monocyte plasticity and heterogeneity.
    Keywords:  bone marrow progenitors and precursors; macrophages; monocyte heterogeneity; monocyte-derived cells; monopoiesis
  15. Exp Hematol. 2024 Apr 03. pii: S0301-472X(24)00074-2. [Epub ahead of print] 104215
      Quiescence and differentiation of hematopoietic stem and progenitor cells (HSPC) can be modified by systemic inflammatory cues. Such cues can not only yield short term changes in HSPCs such as in supporting emergency granulopoiesis but can also promote lasting influences on the HSPC compartment. First, inflammation can be a driver for clonal expansion, promoting clonal hematopoiesis for certain mutant clones, reducing overall clonal diversity, and reshaping the composition of the HSPC pool with significant health consequences. Second, inflammation can generate lasting cell-autonomous changes in HSPCs themselves, leading to changes in the epigenetic state, metabolism, and the function of downstream innate immune cells. This concept, termed "trained immunity," suggests that inflammatory stimuli can alter subsequent immune responses leading to improved innate immunity or, conversely, autoimmunity. Both of these concepts have major implications in human health. Here we review current literature about the lasting effects of inflammation on the HSPC compartment and opportunities for future advancement in this fast-developing field.
    Keywords:  Clonal Hematopoiesis; Hematopoiesis; epigenetics; inflammation; metabolism; trained immunity
  16. Nat Rev Microbiol. 2024 Apr 04.
      The skin barrier protects the human body from invasion by exogenous and pathogenic microorganisms. A breach in this barrier exposes the underlying tissue to microbial contamination, which can lead to infection, delayed healing, and further loss of tissue and organ integrity. Delayed wound healing and chronic wounds are associated with comorbidities, including diabetes, advanced age, immunosuppression and autoimmune disease. The wound microbiota can influence each stage of the multi-factorial repair process and influence the likelihood of an infection. Pathogens that commonly infect wounds, such as Staphylococcus aureus and Pseudomonas aeruginosa, express specialized virulence factors that facilitate adherence and invasion. Biofilm formation and other polymicrobial interactions contribute to host immunity evasion and resistance to antimicrobial therapies. Anaerobic organisms, fungal and viral pathogens, and emerging drug-resistant microorganisms present unique challenges for diagnosis and therapy. In this Review, we explore the current understanding of how microorganisms present in wounds impact the process of skin repair and lead to infection through their actions on the host and the other microbial wound inhabitants.
  17. J Immunol. 2024 Apr 15. 212(8): 1269-1275
      Although the lungs were once considered a sterile environment, advances in sequencing technology have revealed dynamic, low-biomass communities in the respiratory tract, even in health. Key features of these communities-composition, diversity, and burden-are consistently altered in lung disease, associate with host physiology and immunity, and can predict clinical outcomes. Although initial studies of the lung microbiome were descriptive, recent studies have leveraged advances in technology to identify metabolically active microbes and potential associations with their immunomodulatory by-products and lung disease. In this brief review, we discuss novel insights in airway disease and parenchymal lung disease, exploring host-microbiome interactions in disease pathogenesis. We also discuss complex interactions between gut and oropharyngeal microbiota and lung immunobiology. Our advancing knowledge of the lung microbiome will provide disease targets in acute and chronic lung disease and may facilitate the development of new therapeutic strategies.
  18. Front Immunol. 2024 ;15 1396114
    Keywords:  antimicrobial peptides; autophagy; pathogen-associated molecular patterns; phagocytic cells; pyroptosis
  19. Sci Adv. 2024 Apr 05. 10(14): eadk8093
      Trained immunity is one of the mechanisms by which BCG vaccination confers persistent nonspecific protection against diverse diseases. Genomic differences between the different BCG vaccine strains that are in global use could result in variable protection against tuberculosis and therapeutic effects on bladder cancer. In this study, we found that four representative BCG strains (BCG-Russia, BCG-Sweden, BCG-China, and BCG-Pasteur) covering all four genetic clusters differed in their ability to induce trained immunity and nonspecific protection. The trained immunity induced by BCG was associated with the Akt-mTOR-HIF1α axis, glycolysis, and NOD-like receptor signaling pathway. Multi-omics analysis (epigenomics, transcriptomics, and metabolomics) showed that linoleic acid metabolism was correlated with the trained immunity-inducing capacity of different BCG strains. Linoleic acid participated in the induction of trained immunity and could act as adjuvants to enhance BCG-induced trained immunity, revealing a trained immunity-inducing signaling pathway that could be used in the adjuvant development.
  20. Thorax. 2024 Apr 04. pii: thorax-2024-221637. [Epub ahead of print]
    Keywords:  Bacterial Infection; Macrophage Biology; Respiratory Infection; Systemic disease and lungs
  21. Science. 2024 Apr 05. 384(6691): 30-31
      Bronchoconstriction causes epithelial cell extrusion that promotes airway inflammation.
  22. Science. 2024 Apr 04. eadk6200
      Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncover a dominant role for type 2 innate lymphoid cells (ILC2) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2 by androgens leads to a reduction in dendritic cell (DC) accumulation and activation in males, and reduced tissue immunity. Collectively, this work reveals an androgen-ILC2-DC axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.
  23. Am J Respir Cell Mol Biol. 2024 Apr 04.
      Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome (ARDS). Interleukin-10 (IL-10) plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the current study, we have investigated the role of IL-10 in acute lung injury (ALI) induced by influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) coinfection. This unique coinfection model resembles acute pneumonia patients undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor (IL-10R) gene-deficient mice, as well as in vivo neutralizing antibodies, here we show that IL-10 deficiency promotes IFN-γ-dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyper-production and acute mortality. Importantly, this anti-inflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and ARDS pathogenesis by counteracting the IFN-γ response.
    Keywords:  IL-10; Influenza; MRSA; acute lung injury; pneumonia
  24. Discov Immunol. 2023 ;2(1): kyad027
      Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.
    Keywords:  GLUT1; HIF-1α; glucocorticoid; glycolysis; inflammation; macrophage
  25. Science. 2024 Apr 04. eado8542
      Androgen signaling skews skin immunity toward reduced inflammation in male mice.
  26. J Appl Microbiol. 2024 Apr 04. pii: lxae089. [Epub ahead of print]
      RATIONALE: Studies have confirmed that the lung microbiome of lung transplant recipients is altered and serves as a prognostic indicator for long-term mortality. Other studies reported that the lung microbiome affects host immunity and the transcriptome. However, the lung microbiome composition at the early post-transplant period following lung transplantation is unclear, and the relationship of the lung microbiome with pulmonary immunity and the host transcriptome is also not well understood.OBJECTIVES: We hypothesize that changes in the lung microbiome composition in the early post-transplant period may have a predictive value for perioperative outcomes following lung transplantation and that the lung microbiome is correlated with pulmonary immunity and the host transcriptome. Thus, this prospective study aimed at observing the lung microbiome composition in the early post-transplant period and the impact of the lung microbiome on pulmonary cytokines and the host transcriptome. Our findings will help us gain a comprehensive understanding of the distribution and significance of the lung microbiome in the early post-transplant period.
    METHODS: An observational study was conducted to identify the lung microbiome and the host transcriptome characteristics using next-generation sequencing. Luminex was employed for quantifying alveolar cytokines. Spearman's correlation analysis was utilized to assess the impact of the lung microbiome on pulmonary immunity and differentially expressed genes in patients who died perioperatively after lung transplantation.
    RESULTS: Patients with poor perioperative outcomes showed an increase in Mycoplasma and Arcobacter, a decrease of Gemella, and increased interleukin (IL)-10, IL-1β, and tumor necrosis factor (TNF)-α concentration. Lung microbiome correlates with lung immunity in lung transplant recipients. In the death group, the function of differentially expressed genes is associated with cell apoptosis, and promoting TNF production is upregulated. The lung microbiome is related to differentially expressed genes between the two groups.
    CONCLUSIONS: The lung microbiome and cytokines can be considered as potential biomarkers for early prognosis in lung transplant recipients. The lung microbiome is associated with both lung immunity and differentially expressed genes in lung transplant recipients.
    Keywords:  cytokines; lung microbiome; lung transplantation; next-generation sequencing; prognosis
  27. Semin Cell Dev Biol. 2024 Apr 01. pii: S1084-9521(24)00030-2. [Epub ahead of print]161-162 22-30
      Modern precision sequencing techniques have established humans as a holobiont that live in symbiosis with the microbiome. Microbes play an active role throughout the life of a human ranging from metabolism and immunity to disease tolerance. Hence, it is of utmost significance to study the eukaryotic host in conjunction with the microbial antigens to obtain a complete picture of the host-microbiome crosstalk. Previous attempts at profiling host-microbiome interactions have been either superficial or been attempted to catalogue eukaryotic transcriptomic profile and microbial communities in isolation. Additionally, the nature of such immune-microbial interactions is not random but spatially organised. Hence, for a holistic clinical understanding of the interplay between hosts and microbiota, it's imperative to concurrently analyze both microbial and host genetic information, ensuring the preservation of their spatial integrity. Capturing these interactions as a snapshot in time at their site of action has the potential to transform our understanding of how microbes impact human health. In examining early-life microbial impacts, the limited presence of communities compels analysis within reduced biomass frameworks. However, with the advent of spatial transcriptomics we can address this challenge and expand our horizons of understanding these interactions in detail. In the long run, simultaneous spatial profiling of host-microbiome dialogues can have enormous clinical implications especially in gaining mechanistic insights into the disease prognosis of localised infections and inflammation. This review addresses the lacunae in host-microbiome research and highlights the importance of profiling them together to map their interactions while preserving their spatial context.
    Keywords:  Early-life; Host-microbe; Interactions; Microbial-Immune priming; Microbiome; Spatial transcriptomics
  28. Exp Mol Med. 2024 Apr 02.
      Cell death pathways play critical roles in organism development and homeostasis as well as in the pathogenesis of various diseases. While studies over the last decade have elucidated numerous different forms of cell death that can eliminate cells in various contexts, how certain mechanisms impact physiology is still not well understood. Moreover, recent studies have shown that multiple forms cell death can occur in a cell population, with different forms of death eliminating individual cells. Here, we aim to describe the known molecular mechanisms of entosis, a non-apoptotic cell engulfment process, and discuss signaling mechanisms that control its induction as well as its possible crosstalk with other cell death mechanisms.
  29. Curr Opin Microbiol. 2024 Mar 29. pii: S1369-5274(24)00032-8. [Epub ahead of print]79 102456
      Mucosal immunity is posed to constantly interact with commensal microbes and invading pathogens. As a fundamental cell biological pathway affecting immune response, autophagy regulates the interaction between mucosal immunity and microbes through multiple mechanisms, including direct elimination of microbes, control of inflammation, antigen presentation and lymphocyte homeostasis, and secretion of immune mediators. Some of these physiologically important functions do not involve canonical degradative autophagy but rely on certain autophagy genes and their 'autophagy gene-specific functions.' Here, we review the relationship between autophagy and important mucosal pathogens, including influenza virus, Mycobacterium tuberculosis, Salmonella enterica, Citrobacter rodentium, norovirus, and herpes simplex virus, with a particular focus on distinguishing the canonical versus gene-specific mechanisms of autophagy genes.
  30. Cell Commun Signal. 2024 Apr 02. 22(1): 209
      Inflammasomes are complex platforms for the cleavage and release of inactivated IL-1β and IL-18 cytokines that trigger inflammatory responses against damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Gut microbiota plays a pivotal role in maintaining gut homeostasis. Inflammasome activation needs to be tightly regulated to limit aberrant activation and bystander damage to the host cells. Several types of inflammasomes, including Node-like receptor protein family (e.g., NLRP1, NLRP3, NLRP6, NLRP12, NLRC4), PYHIN family, and pyrin inflammasomes, interact with gut microbiota to maintain gut homeostasis. This review discusses the current understanding of how inflammasomes and microbiota interact, and how this interaction impacts human health. Additionally, we introduce novel biologics and antagonists, such as inhibitors of IL-1β and inflammasomes, as therapeutic strategies for treating gastrointestinal disorders when inflammasomes are dysregulated or the composition of gut microbiota changes.
    Keywords:  Canonical; Dysregulation; Gut microbiota; Inflammasome; Non-canonical
  31. Am J Respir Cell Mol Biol. 2024 Apr 04.
    Keywords:  Cystic Fibrosis; Epithelial polarity; TGFbeta pathway; Wnt pathway