Mucosal Immunology最新文献

{"title":"Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.","authors":"Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne","doi":"10.1016/j.mucimm.2024.10.002","DOIUrl":"10.1016/j.mucimm.2024.10.002","url":null,"abstract":"<p><p>The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RelB and C/EBPα critically regulate the development of Peyer's patch mononuclear phagocytes.","authors":"Takashi Kanaya, Toshi Jinnohara, Sayuri Sakakibara, Naoko Tachibana, Takaharu Sasaki, Tamotsu Kato, Marc Riemann, Jianshi Jin, Katsuyuki Shiroguchi, Eiryo Kawakami, Hiroshi Ohno","doi":"10.1016/j.mucimm.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.10.005","url":null,"abstract":"<p><p>To establish protection against harmful foreign antigens, the small intestine harbors guardian sites called Peyer's patches (PPs). PPs take up antigens through microfold (M) cells and transfer them to the sub-epithelial dome (SED), which contains a high density of mononuclear phagocytes (MPs), for T cell-priming. Accumulating evidence indicates that SED-MPs have unique functions other than T cell-priming to facilitate mucosal immune responses; however, the crucial factors regulating the functions of SED-MPs have not been determined. Here we performed transcriptome analysis, and identified the gene signatures of SED-MPs. Further data interpretation with transcription factor (TF) enrichment analysis estimated TFs responsible for the functions of SED-MPs. Among them, we found that RelB and C/EBPα were preferentially activated in SED-MPs. RelB-deficiency silenced the expression of IL-22BP and S100A4 by SED-MPs. On the other hand, C/EBPα-deficiency decreased the expression of lysozyme by SED-MPs, resulting the increased invasion of orally administered pathogenic bacteria into PPs and mesenteric lymph nodes. Our findings thus demonstrate that RelB and C/EBPα are essential to regulate the functions of SED-MPs.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM29 controls enteric RNA virus-induced intestinal inflammation by targeting NLRP6 and NLRP9b signaling pathways.","authors":"Junying Wang, Ling Wang, Wenting Lu, Naser Farhataziz, Anastasia Gonzalez, Junji Xing, Zhiqiang Zhang","doi":"10.1016/j.mucimm.2024.10.004","DOIUrl":"10.1016/j.mucimm.2024.10.004","url":null,"abstract":"<p><p>Infections by enteric virus and intestinal inflammation are recognized as a leading cause of deadly gastroenteritis, and NLRP6 and NLRP9b signaling control these infection and inflammation. However, the regulatory mechanisms of the NLRP6 and NLRP9b signaling in enteric viral infection remain unexplored. In this study, we found that the E3 ligase TRIM29 suppressed type III interferon (IFN-λ) and interleukin-18 (IL-18) production by intestinal epithelial cells (IECs) when exposed to polyinosinic:polycytidylic acid (poly I:C) and enteric RNA viruses. Knockout of TRIM29 in IECs was efficient to restrict intestinal inflammation triggered by the enteric RNA viruses, rotavirus in suckling mice, and the encephalomyocarditis virus (EMCV) in adults. This attenuation in inflammation was attributed to the increased production of IFN-λ and IL-18 in the IECs and more recruitment of intraepithelial protective Ly6A⁺CCR9⁺CD4⁺ T cells in small intestines from TRIM29-deficient mice. Mechanistically, TRIM29 promoted K48-linked ubiquitination, leading to the degradation of NLRP6 and NLRP9b, resulting in decreased IFN-λ and IL-18 secretion by IECs. Our findings reveal that enteric viruses utilize TRIM29 to inhibit IFN-λ and inflammasome activation in IECs, thereby facilitating viral-induced intestinal inflammation. This indicates that targeting TRIM29 could offer a promising therapeutic strategy for alleviating gut diseases.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A reappraisal of IL-9 in inflammation and cancer.","authors":"Fabian Bick, Christophe Blanchetot, Bart N Lambrecht, Martijn J Schuijs","doi":"10.1016/j.mucimm.2024.10.003","DOIUrl":"10.1016/j.mucimm.2024.10.003","url":null,"abstract":"<p><p>While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining T_H9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9's cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensory neuroimmune interactions at the barrier.","authors":"Zhen Wang, Keaton Song, Brian S Kim, John Manion","doi":"10.1016/j.mucimm.2024.10.001","DOIUrl":"10.1016/j.mucimm.2024.10.001","url":null,"abstract":"<p><p>Epithelial barriers such as the skin, lung, and gut, in addition to having unique physiologic functions, are designed to preserve tissue homeostasis upon challenge with a variety of allergens, irritants, or pathogens. Both the innate and adaptive immune systems play a critical role in responding to epithelial cues triggered by environmental stimuli. However, the mechanisms by which organs sense and coordinate complex epithelial, stromal, and immune responses have remained a mystery. Our increasing understanding of the anatomic and functional characteristics of the sensory nervous system is greatly advancing a new field of peripheral neuroimmunology and subsequently changing our understanding of mucosal immunology. Herein, we detail how sensory biology is informing mucosal neuroimmunology, even beyond neuroimmune interactions seen within the central and autonomic nervous systems.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bite-sized immunology; damage and microbes educating immunity at the gingiva","authors":"","doi":"10.1016/j.mucimm.2024.07.004","DOIUrl":"10.1016/j.mucimm.2024.07.004","url":null,"abstract":"<div><div>Immune cells residing at the gingiva experience diverse and unique signals, tailoring their functions to enable them to appropriately respond to immunological challenges and maintain tissue integrity. The gingiva, defined as the mucosal barrier that surrounds and supports the teeth, is the only barrier site completely transected by a hard structure, the tooth. The tissue is damaged in early life during tooth eruption and chronically throughout life by the process of mastication. This occurs alongside challenges typical of barrier sites, including exposure to invading pathogens, the local commensal microbial community and environmental antigens. This review will focus on the immune network safeguarding gingival integrity, which is far less understood than that resident at other barrier sites. A detailed understanding of the gingiva-resident immune network is vital as it is the site of the inflammatory disease periodontitis, the most common chronic inflammatory condition in humans which has well-known detrimental systemic effects. Furthering our understanding of how the immune populations within the gingiva develop, are tailored in health, and how this is dysregulated in disease would further the development of effective therapies for periodontitis.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term alterations in lung epithelial cells after EL-RSV infection exacerbate allergic responses through IL-1β-induced pathways","authors":"","doi":"10.1016/j.mucimm.2024.07.007","DOIUrl":"10.1016/j.mucimm.2024.07.007","url":null,"abstract":"<div><div>Early-life (EL) respiratory infections increase pulmonary disease risk, especially EL-Respiratory Syncytial Virus (EL-RSV) infections linked to asthma. Mechanisms underlying asthma predisposition remain unknown. In this study, we examined the long-term effects on the lung after four weeks post EL-RSV infection. We identified alterations in the lung epithelial cell, with a rise in the percentage of alveolar type 2 epithelial cells (AT2) and a decreased percentage of cells in the AT1 and AT2-AT1 subclusters, as well as upregulation of <em>Bmp2</em> and <em>Krt8</em> genes that are associated with AT2-AT1 <em>trans</em>-differentiation, suggesting potential defects in lung repair processes. We identified persistent upregulation of asthma-associated genes, including <em>Il33</em>. EL-RSV-infected mice allergen-challenged exhibited exacerbated allergic response, with significant upregulation of <em>Il33</em> in the lung and AT2 cells. Similar long-term effects were observed in mice exposed to EL-IL-1β. Notably, treatment with IL-1ra during acute EL-RSV infection mitigated the long-term alveolar alterations and the allergen-exacerbated response. Finally, epigenetic modifications in the promoter of the <em>Il33</em> gene were detected in AT2 cells harvested from EL-RSV and EL-IL1β groups, suggesting that long-term alteration in the epithelium after RSV infection is dependent on the IL-1β pathway. This study provides insight into the molecular mechanisms of asthma predisposition after RSV infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local antigen encounter promotes generation of tissue-resident memory T cells in the large intestine","authors":"","doi":"10.1016/j.mucimm.2024.05.005","DOIUrl":"10.1016/j.mucimm.2024.05.005","url":null,"abstract":"<div><div>Upon infection, CD8⁺ T cells that have been primed in the draining lymph nodes migrate to the invaded tissue, where they receive cues prompting their differentiation into tissue-resident memory cells (Trm), which display niche-specific transcriptional features. Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in specific anatomical niches such as the large intestine (LI). Here, we report that LI Trm-generated following oral infection exhibits a distinct transcriptional profile compared to Trm in other tissues. Notably, we observe that local cues play a crucial role in the preferential establishment of LI Trm, favoring precursors that migrate to the tissue early during infection. Our investigations identify cognate antigen recognition as a major driver of Trm differentiation at this anatomical site. Local antigen presentation not only promotes the proliferation of effector cells and memory precursors but also facilitates the acquisition of transcriptional features characteristic of gut Trm. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activated eosinophils in early life impair lung development and promote long-term lung damage","authors":"","doi":"10.1016/j.mucimm.2024.06.003","DOIUrl":"10.1016/j.mucimm.2024.06.003","url":null,"abstract":"<div><div>Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not been specifically assessed in the context of neonatal lung disease. Furthermore, early life factors including prematurity and respiratory infection predispose infants to chronic obstructive pulmonary disease later in life. To assess eosinophils in the developing lung and how they may contribute to chronic lung disease, we generated mice harboring eosinophil-specific deletion of the negative regulatory enzyme SH2 domain-containing inositol 5′ phosphatase-1. This increased the activity and number of pulmonary eosinophils in the developing lung, which was associated with impaired lung development, expansion of activated alveolar macrophages (AMφ), multinucleated giant cell formation, enlargement of airspaces, and fibrosis. Despite regression of eosinophils following completion of lung development, AMφ-dominated inflammation persisted, alongside lung damage. Bone marrow chimera studies showed that SH2 domain-containing inositol 5′ phosphatase-1-deficient eosinophils were not sufficient to drive inflammatory lung disease in adult steady-state mice but once inflammation and damage were present, it could not be resolved. Depletion of eosinophils during alveolarization alleviated pulmonary inflammation and lung pathology, demonstrating an eosinophil-intrinsic effect. These results show that the presence of activated eosinophils during alveolarization aggravates AMφs and promotes sustained inflammation and long-lasting lung pathology.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary protein modulates intestinal dendritic cells to establish mucosal homeostasis","authors":"","doi":"10.1016/j.mucimm.2024.06.006","DOIUrl":"10.1016/j.mucimm.2024.06.006","url":null,"abstract":"<div><div>Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in <em>Akkermansia muciniphilia</em> and <em>Oscillibacter</em> and a decrease in <em>Lactococcus lactis</em> and <em>Bifidobacterium</em>. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}