Mucosal Immunology最新文献

{"title":"Triggering mouth-resident antiviral CD8⁺ T cells potentiates experimental periodontitis.","authors":"Flávia M Saavedra, Danielle B Brotto, Vineet Joag, Courtney A Matson, Pavel P Nesmiyanov, Mark C Herzberg, Vaiva Vezys, David Masopust, J Michael Stolley","doi":"10.1016/j.mucimm.2025.02.003","DOIUrl":"10.1016/j.mucimm.2025.02.003","url":null,"abstract":"<p><p>Emerging evidence indicates that gingival-resident helper CD4⁺ T cells are major drivers of periodontal inflammation in response to commensal and pathogenic oral microorganisms. Whether tissue-resident memory CD8⁺ T cells (T_RM), which principally safeguard against viruses and cancer but also drive certain autoimmune and inflammatory conditions, impact periodontitis progression and severity remain unknown. We asked whether local reactivation of oral CD8⁺ T_RM of a defined antigen specificity could exacerbate ligature-induced periodontitis (LIP), a well-established model of periodontal disease in mice. Topical application of virus-mimicking peptides to the oral mucosa concurrent with LIP 1) intensified alveolar bone loss, 2) amplified gingival and cervical lymph node inflammation, and 3) stimulated gingival transcriptional changes in genes related to innate immune sensing and cell-mediated cytotoxicity. Therapeutic depletion of CD103-expressing oral CD8⁺ T_RM in advance of LIP prevented exacerbation of disease. These observations provide evidence that oral CD103⁺ CD8⁺ T_RM have the potential to participate in gingival inflammation, alveolar bone loss, and periodontitis.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483673","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":"Lung-resident memory Th2 cells regulate pulmonary cryptococcosis by inducing type-II granuloma formation.","authors":"Keigo Ueno, Akiko Nagamori, Nahoko Oniyama Honkyu, Kyung J Kwon-Chung, Yoshitsugu Miyazaki","doi":"10.1016/j.mucimm.2025.02.004","DOIUrl":"10.1016/j.mucimm.2025.02.004","url":null,"abstract":"<p><p>Lung-resident memory T cells (lung TRMs) settle in the lung and respond rapidly to external antigens, and are therefore considered to have great potential for development of respiratory vaccines. Here, we demonstrate that lung-resident memory Th2 cells (lung TRM2) protect against pulmonary mycosis caused by Cryptococcus gattii. We developed novel whole-cell intranasal vaccines using a heat-inactivated C.gattii capsule-deficient strain cap59Δ, which induced ST-2⁺ Gata-3⁺ lung TRM2 specifically responding to C.gattii whole-cell antigen. Lung fungal burden and survival rate were significantly improved in immunized mice after infection challenge. The immunosuppressive agent FTY720 did not impact vaccine effectiveness, and adoptive transfer of lung TRMs into Rag-1-deficient mice decreased the lung fungal burden. In IL-4/IL-13 double-knockout (DKO) mice, immunization did not efficiently induce eosinophil recruitment and granuloma formation, and the fungal burden was not decreased after infection challenge. Co-culture of lung TRM2 with myeloid lineages induced multinucleated giant cells (MGCs) in the presence of antigen, which phagocytosed live C.gattii cells without opsonization, whereas lung TRM2 from DKO mice did not induce MGCs. These findings provide a new model in which lung TRM2 suppress C.gattii infection via granuloma induction.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472230","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":"Influenza virus-induced type I interferons disrupt alveolar epithelial repair and tight junction integrity in the developing lung.","authors":"Abigail P Onufer, Joshua Chang Mell, Laura Cort, Abhishek Rao, Nontokozo V Mdluli, Alison J Carey","doi":"10.1016/j.mucimm.2025.02.002","DOIUrl":"10.1016/j.mucimm.2025.02.002","url":null,"abstract":"<p><p>Recently, we demonstrated that influenza A virus (IAV)-infected murine neonates lacking a functional IFN-I receptor (IFNAR^-/-) had significantly improved survival and reduced lung pathology relative to wild-type (WT) neonates. In direct contrast, adult IFNAR^-/- mice display enhanced morbidity following IAV infection relative to WT adults. We hypothesized that IAV-induced IFN-I signaling in primary neonatal type II alveolar epithelial cells (TIIECs), the main cell type of IAV infection and initiator of host response in the lung, contributed to age-specific viral pathogenesis. Multifactorial transcriptional analysis of purified TIIECs revealed age, not infection status, as the primary driver of transcriptional differences in TIIECs. Subsequent pathway analysis demonstrated IAV-infected IFNAR^-/- neonates significantly upregulated cell proliferation, tissue repair and tight junction genes at 2-days post-infection (dpi), compared to WT neonates. Next, to determine if these growth and repair differences persisted later in infection, targeted analysis of repair gene expression and immunofluorescent quantification of pulmonary sealing tight junction molecules ZO-1 and occludin was performed at 6-dpi. Relative to WT neonates, IFNAR^-/- neonates had significantly higher whole lung occludin staining and repair gene expression. Together, our data demonstrates IFN-I signaling is extremely pathogenic in the developing lung by disrupting alveolar repair and pulmonary barrier integrity.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472767","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":"IL-6 mediates defense against influenza virus by promoting protective antibody responses but not innate inflammation.","authors":"F Piattini, N D Sidiropoulos, I Berest, M Kopf","doi":"10.1016/j.mucimm.2025.02.001","DOIUrl":"10.1016/j.mucimm.2025.02.001","url":null,"abstract":"<p><p>Influenza virus infection is a leading cause of morbidity and mortality worldwide, posing a significant public health problem. The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown to promote defense against respiratory viral infection, while excessive IL-6 responses have been associated with severe pneumonia. Heterogenous expression of IL-6R and the IL-6-signal transducer subunit (gp130) across many cell types and different signaling modalities have made it difficult to define the precise role of the IL-6/IL-6R pathway in vivo. We generated multiple cell lineage-specific Il6ra-deficient mice and compared them to global Il6ra^-/- and Il-6^-/- mice to dissect the systemic and cell-intrinsic mechanisms for pneumonitis and control of influenza A virus (IAV) infection. Delayed viral clearance and severe morbidity in the global IL-6 knockouts were associated with reduced antibody responses, complement C3 and C5 production, and impaired T follicular helper (Tfh) cell generation. Mice lacking IL-6R exclusively in T cells phenocopied a defect in Tfh cell differentiation and antibody production, although susceptibility to IAV was only mildly affected. Mice lacking IL-6R specifically in B cells mounted normal antibody responses. Moreover, innate pro-inflammatory cytokine responses, myeloid cell infiltration, and adaptive immunity in the lung remained unaffected in Il6ra^fl/flLysM^Cr^e mice. Our results suggest that IL-6 mediates defense against IAV mainly by generating Tfh cells and promoting local C3 production, which together are required for eliciting protective antibody responses by B cells.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468598","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":"Antibiotic-induced dysbiosis of the ocular microbiome affects corneal circadian rhythmic activity in mice.","authors":"Xinwei Jiao, Yan Li, Yu Hu, Ruyu Yan, Ting Fu, Jun Liu, Zhijie Li","doi":"10.1016/j.mucimm.2025.01.010","DOIUrl":"10.1016/j.mucimm.2025.01.010","url":null,"abstract":"<p><p>The ocular surface microbiota plays a critical role in maintaining corneal homeostasis, but its disruption and subsequent effects on corneal functions remain poorly understood. This study investigates how antibiotic-induced microbial depletion affects the corneal circadian transcriptome in C57BL/6J mice. Dysbiosis was induced using a topical antibiotic cocktail, and RNA sequencing was employed to analyze gene expression across eight time points over 24 h. Antibiotic treatment disrupted corneal circadian rhythms, eliminating rhythmicity in 1,812 genes and introducing rhythmicity in 1,928 previously arrhythmic genes. Furthermore, epithelial adhesion was impaired, inflammation was elevated, and neural sensitivity was reduced. More than 50 % of ocular microbial genera exhibited daily oscillations, with six genera showing significant correlations with corneal rhythmic transcripts. Additionally, the administration of TLR agonists restored circadian gene expression patterns, with partial recovery of corneal barrier function and immune homeostasis, further highlighting the potential of microbiota-targeted therapies in treating ocular surface disorders. These findings underscore the critical role of the ocular microbiota in regulating corneal health and suggest that restoring microbial balance via TLR activation may offer new therapeutic avenues for eye diseases.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374452","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":"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":"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}