Mucosal Immunology最新文献

Laboratory mice raised under specific-pathogen-free (SPF) conditions experience restricted microbial and antigenic exposure, which favours an immature immune system and limits their translational value for respiratory research. While microbial enrichment in "dirty" mouse models restores immune maturation, its impact on integrated respiratory function and model transferability to human disease remains understudied. Here, we tested whether ecological exposure through indoor rewilding of SPF-reared mice could reshape immune complexity and recalibrate pulmonary physiology. Two-month-old female C57BL/6J mice were housed for three months under SPF or indoor-rewilding conditions and assessed for immune, mechanical, and systemic parameters. Rewilded mice exhibited expanded pulmonary immune subsets, increased dendritic-cell immune checkpoint, with TNF/IFN-γ activation coupled to regulatory IL-10 signaling. Despite sustained exposure, the alveolar-capillary barrier integrity was preserved. Functionally, respiratory oscillometry revealed improved pulmonary mechanics, including lower airway resistance, higher compliance, and reduced airway responsiveness to methacholine. Systemic cytokine analyses indicated compartmentalized pulmonary immune activation, maintaining an overall anti-inflammatory balance. Importantly, PRIA screening detected no reportable pathogens introduced during rewilding, while cecal shotgun metagenomics confirmed microbial enrichment. Together, these findings demonstrate that indoor rewilding reestablishes coordinated lung immune and mechanical homeostasis in SPF-reared mice, providing a safe and scalable model for studying human-like mucosal immunity and respiratory physiology with broad implications for preclinical respiratory research and therapeutic testing.

Group 2 innate lymphoid cells (ILC2s) contribute to mucosal homeostasis and initiate immune responses against gastrointestinal pathogens, including those that target the stomach. However, the role of commensal bacteria in promoting stomach immunity is unknown. Here, we report that YL27, a commensal bacterium from the family Muribaculaceae, modulates stomach ILC2s and their associated immune effector functions. Activation of stomach ILC2s was initiated by a subset of IL-33-producing fibroblasts in response to acetate, a metabolite of YL27, via its receptor GPR43. ILC2s-derived IL-13 was required for the induction of Muc1 expression in the epithelium and contributed to protection from H. pylori infection. Thus, these findings demonstrate that ILC2s-mediated immune responses in the stomach are initiated by interactions between commensal bacteria and fibroblasts, and highlight the role of commensals in the innate response to pathogenic bacteria for the first line of mucosal defense.

EPICERTIN, a modified cholera toxin B subunit (CTB), facilitates mucosal healing in preclinical colitis models, but its anti-inflammatory mechanisms remain unclear. Here, we investigated EPICERTIN's effects on macrophages. In a dextran sulfate sodium-induced colitis mouse model, oral administration of EPICERTIN reduced neutrophil infiltration and increased CX3CR1⁺MHCII^lo/- (M2-like) over CX3CR1⁺MHCII^hi (M1-like) macrophages in the colon lamina propria. This was concurrent with upregulation of colony-stimulating factor 2 (Csf2) and growth factors (Egf, TgfA, Fgf, Pdgf) involved in mucosal remodeling. Similarly, in colon tissue from a human with active colitis, EPICERTIN significantly upregulated CSF2 and tissue repair-associated genes while downregulating proinflammatory genes (IL1B, IL6ST). In vitro, EPICERTIN promoted macrophage survival under serum-free conditions, whereas CTB induced apoptosis in murine RAW264.7 cells, peritoneal macrophages, and human THP-1 cells. Remarkably, EPICERTIN protected macrophages from apoptosis induced by chemical ER-stressors or lipopolysaccharides. Additionally, EPICERTIN downregulated cell surface molecules HLA-DR, CD14, CD80, and CD86 in THP-1 cells and modestly upregulated chemokines and proinflammatory cytokines genes as well as TGFB1 in human PBMC-derived macrophages. In contrast, CTB strongly increased proinflammatory genes and activation markers. These findings indicate that EPICERTIN promotes macrophage homeostasis by inducing a less inflammatory, pro-remodeling phenotype, whereas CTB may trigger activation-induced cell death.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and defined by formation of granulomas, immune aggregates that can restrict or support bacterial replication. Macrophages are fundamental components of granulomas and TB pathogenesis, yet their population structure and functional diversity is incompletely understood. The interaction between macrophages and Mtb in vivo, including which cell subsets are infected and how they respond to colonization, is a major determinant of disease outcome. Here, we profiled lung tissue and granulomas from Mtb-infected cynomolgus macaques, an animal model that closely recapitulates human TB, to define macrophage biology in the early stage of infection. We identified distinct subsets, including embryonic-origin tissue resident alveolar macrophages (AMs), monocyte-derived AMs, and interstitial macrophages with distinct spatial localization in granulomas. Tissue-resident AMs and a novel macrophage subset undergoing epithelial-to-mesenchymal transition were the most frequently infected cells in lung tissue. Mtb-infected cells specifically expressed immune-related and migration-associated genes, suggesting that Mtb induces or exploits these pathways in early infection as a survival strategy in vivo. Our findings highlight the complex interplay between macrophage heterogeneity and functional states that serve as a driver of susceptibility to Mtb infection and TB progression.

The spatial localization of CD4+ T cells within the Mycobacterium tuberculosis (Mtb)-infected lung is critical for optimal immunity. Here, we investigate the role of two E-cadherin binding receptors, CD103 and KLRG1. We demonstrate that KLRG1 restricts CD4+ T cells to the lung vasculature early during infection, and limits lesion homing at chronic stages. Subunit vaccination diminishes KLRG1 expression and increases CD103+ CD4+ T cells associated with improved bacterial control. We identify a link between CD103 expression and Th17 differentiation, as vaccine-induced Th17 cells display increased propensity to upregulate CD103 in the lung. Mixed bone marrow chimeras reveal that CD103 promotes tissue retention and localization of CD4+ T cells in close proximity to Mtb, facilitating enhanced TCR signaling. In contrast, CD103-deficient cells remain confined to the lesion periphery with decreased TCR activation. These findings highlight the importance of CD103 in CD4+ T cell localization and antigen-sensing with implications for vaccine design.

A finely tuned immune regulation within the epididymis and testis is essential for male reproductive health. This balance is especially critical in the epididymis, where sperm mature and ascending infections frequently disrupt homeostasis, resulting in regionally different immune responses and potential long-term fertility impairments. We previously demonstrated that the epididymis harbors a region-specific immunological scaffold, with CX3CR1⁺ macrophages as the most prominent epithelium-associated immune cell population. Here, we established a transgenic mouse model to selectively deplete these intraepithelial CX3CR1⁺ macrophages within the epididymis, resulting in focal epithelial damage and impaired sperm maturation processes essential for proper sperm functionality. Additionally, a mild reduction of the testicular macrophage pool resulted in transient disruptions in spermatogenesis and steroidogenesis. Although the macrophage niche was repopulated after depletion, the newly recruited cells displayed altered phenotypes consistent with persistent sperm alterations. Following infection with uropathogenic Escherichia coli (UPEC) macrophage-depleted mice exhibited exacerbated immune responses - particularly in normally protected proximal epididymal regions - with earlier onset and more severe tissue damage. Transcriptomic analysis revealed a failure to restrain inflammatory responses, especially in genes involved in immune regulation and antibacterial defense, accompanied by elevated immune cell infiltration in infected macrophage-depleted mice. Overall, our findings confirm a crucial role for CX3CR1⁺ macrophages in preserving epithelial integrity and modulating immune responses, supporting a stable tissue environment necessary for efficient organ function of both epididymis and testis.

Paneth cells are secretory intestinal epithelial cells most abundant in the ileum that contribute to gut homeostasis and innate immunity through secretion of antimicrobial peptides and intestinal stem cell factors. Dysfunction of Paneth cells has been implicated in various gastrointestinal disorders. Although regulation of Paneth cell function by microbial signals has been well established, accumulating evidence highlights a pivotal role for cytokine networks in modulating Paneth cell activity. Cytokines such as Interferons (IFNs), Interleukin (IL)-9, IL-13, IL-17, IL-22, and tumor necrosis factor (TNF) influence diverse aspects of Paneth cell biology and, in turn, intestinal tissue homeostasis. In this review, we synthesize current knowledge of cytokine-mediated regulation of Paneth cells, explore the emerging role of Paneth cell phenotyping as predictive in intestinal disease outcomes, and conclude with key unanswered questions that define future research directions in the field.

The relationship between the intestinal microbiota and the mucosal immune system is a key determinant of health in that it plays a pivotal role in managing pathogens and avoiding chronic inflammatory diseases. Diet is a central mediator of this relationship, influencing microbiota composition as well as the function of gut bacteria and host cells. This article will review impacts of the myriad of dietary components capable of influencing the microbiota-immune system interrelationship. Such components include macronutrients, micronutrients, phytochemicals, fibers naturally present in traditional foods as well the array of food additives, including sweeteners, metals, fibers and emulsifiers that are widely incorporated into highly processed foods. We will discuss how presence and/or absence of these food components impacts health-related outcomes in mice, and mechanisms that might underlie these outcomes, including the role of the microbiota therein. We will also discuss emerging approaches to better understand the microbiota-immune system-diet interrelationship, including how they can be leveraged to improve health of humans.

Secondary bacterial pneumonia causes substantial morbidity and mortality following influenza A virus (IAV) infection, yet no therapies exist that address the underlying immune dysfunction and epithelial damage that predispose to bacterial superinfection. Here, we demonstrate that short-course intranasal treatment with LAT9997, a synthetic peptide derived from human growth hormone, protects against severe IAV infection and subsequent Streptococcus pneumoniae superinfection. Significantly, just two intranasal doses administered on days 1 and 2 post-IAV infection, with no further treatment, improved survival from 0% to 85%, reduced bacterial burden in the airways, and markedly attenuated lung pathology. Mechanistically, LAT9997 selectively suppressed epithelial AKT Ser473 phosphorylation, rebalancing infection-induced signalling to reduce viral dissemination, limit lung damage, and preserve barrier integrity during the viral phase. This early intervention established a protective airway immune environment characterized by preserved alveolar macrophages, restrained neutrophil recruitment, and reduced inflammatory mediators. During subsequent bacterial challenge, innate immune cells displayed phenotypic markers of controlled activation, including enhanced neutrophil viability, reduced inflammatory surface markers, and restrained protease activity, occurring without broad alterations in cell numbers. These findings provide proof-of-concept that brief, host-directed therapy during acute viral infection can durably prevent post-viral bacterial pneumonia by modulating lung immunity and preserving barrier integrity.

Two studies in Nature Immunology by Jakob, Sterczyk et al. and Pirzgalska et al. show that neuron-derived vasoactive intestinal peptide (VIP) regulates intestinal epithelial differentiation and orchestrates immune responses. Through its receptor VIPR1, VIP restrains secretory lineage expansion, balances type 1 and type 2 immunity, and establishes a neuro-epithelial circuit preserving gut barrier integrity.