Mucosal Immunology最新文献

{"title":"CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis","authors":"Taylor M. Benson ,&nbsp;Gary E. Markey ,&nbsp;Juliet A. Hammer ,&nbsp;Luke Simerly ,&nbsp;Monika Dzieciatkowska ,&nbsp;Kimberly R. Jordan ,&nbsp;Kelley E. Capocelli ,&nbsp;Kathleen M. Scullion ,&nbsp;Louise Crowe ,&nbsp;Sinéad Ryan ,&nbsp;Jennifer O. Black ,&nbsp;Taylor Crue ,&nbsp;Rachel Andrews ,&nbsp;Cassandra Burger ,&nbsp;Eóin N. McNamee ,&nbsp;Glenn T. Furuta ,&nbsp;Calies Menard-Katcher ,&nbsp;Joanne C. Masterson","doi":"10.1016/j.mucimm.2024.09.006","DOIUrl":"10.1016/j.mucimm.2024.09.006","url":null,"abstract":"<div><div>Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 (<em>L2-IL5^OXA</em>). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the <em>L2-IL5^OXA</em> mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 105-120"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350419","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":"TRIM29 controls enteric RNA virus-induced intestinal inflammation by targeting NLRP6 and NLRP9b signaling pathways","authors":"Junying Wang ,&nbsp;Ling Wang ,&nbsp;Wenting Lu ,&nbsp;Naser Farhataziz ,&nbsp;Anastasia Gonzalez ,&nbsp;Junji Xing ,&nbsp;Zhiqiang Zhang","doi":"10.1016/j.mucimm.2024.10.004","DOIUrl":"10.1016/j.mucimm.2024.10.004","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 135-150"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-inflammatory NK-like T cells are expanded in the blood and inflamed intestine in Crohn’s disease","authors":"Cristina M. Chiarolla ,&nbsp;Axel R. Schulz ,&nbsp;Michael Meir ,&nbsp;Sebastian Ferrara ,&nbsp;Yin Xiao ,&nbsp;Simone Reu-Hofer ,&nbsp;Addi J. Romero-Olmedo ,&nbsp;Valeria Falcone ,&nbsp;Katja Hoffmann ,&nbsp;Maike Büttner-Herold ,&nbsp;Martina Prelog ,&nbsp;Andreas Rosenwald ,&nbsp;Hartmut Hengel ,&nbsp;Michael Lohoff ,&nbsp;Hyun-Dong Chang ,&nbsp;Nicolas Schlegel ,&nbsp;Henrik E. Mei ,&nbsp;Friederike Berberich-Siebelt","doi":"10.1016/j.mucimm.2024.11.001","DOIUrl":"10.1016/j.mucimm.2024.11.001","url":null,"abstract":"<div><div>Altered intestinal immune homeostasis leads to chronic inflammation in Crohn’s disease (CD). To address disease- and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with CD and healthy donors’ PBMCs. Chronic intestinal inflammation enforced activation, exhaustion, and terminal differentiation of CD4⁺ and CD8⁺ T cells and a relative enrichment of CD4⁺ regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4⁺FOXP3⁺HLA-DR⁺TIGIT^– and CD4⁺FOXP3⁺CD56⁺, expressing pro-inflammatory IFN-γ upon <em>in vitro</em> stimulation. Some conventional T (Tcon) cells acquired NK-like features. In CD patients’ blood, not well studied CD16⁺CCR6⁺CD127⁺ T cells appeared, being CD4⁺ or CD8⁺, a phenotype inducible on healthy T cells by CD blood plasma. Upon CD16-mediated antibody binding, they could attain effector function. These findings suggest an uncommon pro-inflammatory innate-like differentiation of Treg and Tcon cells with acquisition of non-specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 162-175"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623077","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":"IgA facilitates the persistence of the mucosal pathogen Helicobacter pylori","authors":"Mariela Artola-Borán ,&nbsp;Lydia Kirsche ,&nbsp;Angela Fallegger ,&nbsp;Peter Leary ,&nbsp;Mine Tanriover ,&nbsp;Tanja Goodwin ,&nbsp;Gavin Geiger ,&nbsp;Siegfried Hapfelmeier ,&nbsp;Shida Yousefi ,&nbsp;Hans-Uwe Simon ,&nbsp;Isabelle C. Arnold ,&nbsp;Anne Müller","doi":"10.1016/j.mucimm.2024.11.006","DOIUrl":"10.1016/j.mucimm.2024.11.006","url":null,"abstract":"<div><div>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 <em>Helicobacter pylori</em> and <em>Citrobacter rodentium</em>. 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 <em>H. pylori</em>, 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 <em>C. rodentium</em> in all examined tissues, suffer from more severe weight loss and develop more colitis. In contrast, <em>H. pylori</em> 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 <em>H. pylori</em> 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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 232-247"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710604","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":"There's no place like home: How local tissue microenvironments shape the function of innate lymphoid cells.","authors":"Luke B Roberts, Alanna M Kelly, Matthew R Hepworth","doi":"10.1016/j.mucimm.2025.01.012","DOIUrl":"10.1016/j.mucimm.2025.01.012","url":null,"abstract":"<p><p>Innate lymphoid cells (ILC) have emerged as critical immune effectors with key roles in orchestrating the wider immune response. While ILC are relatively rare cells they are found enriched within discrete microenvironments, predominantly within barrier tissues. An emerging body of evidence implicates complex and multi-layered interactions between cell types, tissue structure and the external environment as key determinants of ILC function within these niches. In this review we will discuss the specific components that constitute ILC-associated microenvironments and consider how they act to determine health and disease. The development of holistic, integrated models of ILC function within complex tissue environments will inform new understanding of the contextual cues and mechanisms that determine the protective versus disease-causing roles of this immune cell family.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122993","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":"The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction","authors":"Wan-Bing Dai ,&nbsp;Xiao Zhang ,&nbsp;Xu-Liang Jiang ,&nbsp;Yi-Zhe Zhang ,&nbsp;Ling-Ke Chen ,&nbsp;Wei-Tian Tian ,&nbsp;Xiao-Xin Zhou ,&nbsp;Xiao-Yu Sun ,&nbsp;Li-Li Huang ,&nbsp;Xi-Yao Gu ,&nbsp;Xue-Mei Chen ,&nbsp;Xiao-Dan Wu ,&nbsp;Jie Tian ,&nbsp;Wei-Feng Yu ,&nbsp;Lei Shen ,&nbsp;Dian-San Su","doi":"10.1016/j.mucimm.2024.09.002","DOIUrl":"10.1016/j.mucimm.2024.09.002","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut–brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) expression and activity, which shifts intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1–KYN pathway in the intestine could be a promising therapeutic target for POCD.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 53-65"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183289","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":"RelB and C/EBPα critically regulate the development of Peyer’s patch mononuclear phagocytes","authors":"Takashi Kanaya ,&nbsp;Toshi Jinnohara ,&nbsp;Sayuri Sakakibara ,&nbsp;Naoko Tachibana ,&nbsp;Takaharu Sasaki ,&nbsp;Tamotsu Kato ,&nbsp;Marc Riemann ,&nbsp;Jianshi Jin ,&nbsp;Katsuyuki Shiroguchi ,&nbsp;Eiryo Kawakami ,&nbsp;Hiroshi Ohno","doi":"10.1016/j.mucimm.2024.10.005","DOIUrl":"10.1016/j.mucimm.2024.10.005","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 151-161"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt/β-catenin maintains epithelial IL-33 in the colonic stem and progenitor cell niche and drives its induction in colitis","authors":"Michael A. Schumacher ,&nbsp;Megan H. Thai ,&nbsp;Jonathan J. Hsieh ,&nbsp;Alexa Gramajo ,&nbsp;Cambrian Y. Liu ,&nbsp;Mark R. Frey","doi":"10.1016/j.mucimm.2024.11.007","DOIUrl":"10.1016/j.mucimm.2024.11.007","url":null,"abstract":"<div><div>Interleukin (IL)–33 is a key responder to intestinal injury and inflammation. In the colon, it is expressed by several cell populations, with the specific cellular source likely determining its role. The colonic epithelium expresses IL-33; however, the factors controlling its production and the specific epithelial lineage(s) expressing IL-33 are poorly understood. We recently reported that colonic epithelial IL-33 is induced by inhibition of glycogen synthase kinase-3β (GSK3β), but the signaling pathway mediating this induction is unknown. Here we tested the role of Wnt/β-catenin signaling in regulating colonic epithelial IL-33 at homeostasis and in injury-induced colitis. Transcriptomic analysis shows that epithelial IL-33 localizes to stem and progenitor cells. Ligand activation of Wnt/β-catenin signaling induced IL-33 in colonic organoid and cell cultures. Furthermore, small-molecule disruption of β-catenin interaction with cyclic AMP response element binding protein (CBP) prevented epithelial IL-33 induction. Antagonism of CBP/β-catenin signaling also prevented rapid epithelial IL-33 induction in dextran sodium sulfate (DSS)-mediated colitis, and was associated with maintenance of crypt-expressed host defense peptides. Together, these findings show β-catenin-driven production of epithelial IL-33 is an early response to colonic injury that shapes the crypt base defense response and suggest an immunoregulatory role for the stem cell niche in tissue injury.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 248-256"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730715","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":"Tear duct M cells exacerbate allergic conjunctivitis by facilitating germinal-center reactions.","authors":"Yuki Oya, Shunsuke Kimura, Maho Uemura, Yumiko Fujimura, Koji Hase","doi":"10.1016/j.mucimm.2025.01.009","DOIUrl":"10.1016/j.mucimm.2025.01.009","url":null,"abstract":"<p><p>The ocular mucosal surface regularly encounters external materials in the air and tear fluids. Microfold (M) cells, specialized epithelial cells for antigen uptake, are present in tear duct-associated lymphoid tissue (TALT) within the nasolacrimal sac; however, their immunological significance is unclear. We generated Krt5-Cre Tnfrsf11a^flox/flox mice, which lack functional M cells in the TALT, as evidenced by the absence of M-cell markers and reduced nanoparticle uptake. M cell deficiency resulted in fewer T follicular helper (Tfh) and germinal center (GC) B cells in the TALT under steady-state conditions. Upon induction of allergic conjunctivitis, control mice exhibited itching and increased Tfh and immunoglobulin E (IgE⁺) GC B cells in the TALT. However, M cell-deficient mice showed ameliorated allergic symptoms with fewer Tfh and IgE⁺ GC B cells. These findings suggest that M cells in TALT contribute to ocular surface immunosurveillance, whereas, upon allergen exposure, they play a critical role in the development of allergic conjunctivitis.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122946","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":"Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner","authors":"Maria-Bernadette Madel ,&nbsp;Lidia Ibáñez ,&nbsp;Thomas Ciucci ,&nbsp;Julia Halper ,&nbsp;Antoine Boutin ,&nbsp;Ghada Beldi ,&nbsp;Alice C. Lavanant ,&nbsp;Henri-Jean Garchon ,&nbsp;Matthieu Rouleau ,&nbsp;Christopher G. Mueller ,&nbsp;Laurent Peyrin-Biroulet ,&nbsp;David Moulin ,&nbsp;Claudine Blin-Wakkach ,&nbsp;Abdelilah Wakkach","doi":"10.1016/j.mucimm.2024.09.005","DOIUrl":"10.1016/j.mucimm.2024.09.005","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn’s disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 90-104"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350420","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}