Pub Date : 2025-02-05DOI: 10.1016/j.mucimm.2025.01.010
Xinwei Jiao, Yan Li, Yu Hu, Ruyu Yan, Ting Fu, Jun Liu, Zhijie Li
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.
{"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}
Pub Date : 2025-02-05DOI: 10.1016/j.mucimm.2025.01.013
Zhijie Wang, Zixuan He, Xin Chang, Lu Xie, Yihang Song, Haicong Wu, Hao Zhang, Shuling Wang, Xiaofeng Zhang, Yu Bai
Mitochondria are key regulators of inflammatory responses and mitochondrial dysfunction is closely linked to various inflammatory diseases. Increasing genetic and experimental evidence suggests that mitochondria play a critical role in inflammatory bowel disease (IBD). In the complex environment of the intestinal tract, intestinal epithelial cells (IECs) and their mitochondria possess unique phenotypic features, shaping each other and regulating intestinal homeostasis and inflammation through diverse mechanisms. Here, we focus on intestinal inflammation in IBD induced by mitochondrial damage-associated molecular patterns (mtDAMPs), which comprise mitochondrial components and metabolic products. The pathogenic mechanisms of mtDAMP signaling pathways mediated by two major mtDAMPs, mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), are discussed.
{"title":"Mitochondrial damage-associated molecular patterns: New perspectives for mitochondria and inflammatory bowel diseases.","authors":"Zhijie Wang, Zixuan He, Xin Chang, Lu Xie, Yihang Song, Haicong Wu, Hao Zhang, Shuling Wang, Xiaofeng Zhang, Yu Bai","doi":"10.1016/j.mucimm.2025.01.013","DOIUrl":"10.1016/j.mucimm.2025.01.013","url":null,"abstract":"<p><p>Mitochondria are key regulators of inflammatory responses and mitochondrial dysfunction is closely linked to various inflammatory diseases. Increasing genetic and experimental evidence suggests that mitochondria play a critical role in inflammatory bowel disease (IBD). In the complex environment of the intestinal tract, intestinal epithelial cells (IECs) and their mitochondria possess unique phenotypic features, shaping each other and regulating intestinal homeostasis and inflammation through diverse mechanisms. Here, we focus on intestinal inflammation in IBD induced by mitochondrial damage-associated molecular patterns (mtDAMPs), which comprise mitochondrial components and metabolic products. The pathogenic mechanisms of mtDAMP signaling pathways mediated by two major mtDAMPs, mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), are discussed.</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":"143374453","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.09.006
Taylor M. Benson , Gary E. Markey , Juliet A. Hammer , Luke Simerly , Monika Dzieciatkowska , Kimberly R. Jordan , Kelley E. Capocelli , Kathleen M. Scullion , Louise Crowe , Sinéad Ryan , Jennifer O. Black , Taylor Crue , Rachel Andrews , Cassandra Burger , Eóin N. McNamee , Glenn T. Furuta , Calies Menard-Katcher , Joanne C. Masterson
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 (L2-IL5OXA). 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 L2-IL5OXA 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.
{"title":"CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis","authors":"Taylor M. Benson , Gary E. Markey , Juliet A. Hammer , Luke Simerly , Monika Dzieciatkowska , Kimberly R. Jordan , Kelley E. Capocelli , Kathleen M. Scullion , Louise Crowe , Sinéad Ryan , Jennifer O. Black , Taylor Crue , Rachel Andrews , Cassandra Burger , Eóin N. McNamee , Glenn T. Furuta , Calies Menard-Katcher , 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<sup>OXA</sup></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<sup>OXA</sup></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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.10.004
Junying Wang , Ling Wang , Wenting Lu , Naser Farhataziz , Anastasia Gonzalez , Junji Xing , Zhiqiang Zhang
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.
{"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":"<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<sup>+</sup>CCR9<sup>+</sup>CD4<sup>+</sup> 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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.11.001
Cristina M. Chiarolla , Axel R. Schulz , Michael Meir , Sebastian Ferrara , Yin Xiao , Simone Reu-Hofer , Addi J. Romero-Olmedo , Valeria Falcone , Katja Hoffmann , Maike Büttner-Herold , Martina Prelog , Andreas Rosenwald , Hartmut Hengel , Michael Lohoff , Hyun-Dong Chang , Nicolas Schlegel , Henrik E. Mei , Friederike Berberich-Siebelt
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 in vitro 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.
肠道免疫平衡的改变导致了克罗恩病（CD）的慢性炎症。针对疾病和组织特异性改变，我们对克罗恩病患者的外周和肠道淋巴细胞以及健康供体的 PBMCs 进行了以 T 细胞为中心的质谱分析。慢性肠道炎症导致 CD4+ 和 CD8+ T 细胞活化、衰竭和终末分化，CD4+ 调节性 T（Treg）细胞相对富集。此外，炎症时还会出现神秘的稀有 Treg 亚群，如 CD4+FOXP3+HLA-DR+TIGIT- 和 CD4+FOXP3+CD56+，体外刺激时可表达促炎性 IFN-γ。一些常规 T（Tcon）细胞具有类似 NK 的特征。在 CD 患者的血液中，出现了研究不多的 CD16+CCR6+CD127+ T 细胞，它们是 CD4+ 或 CD8+，这是 CD 血浆在健康 T 细胞上诱导的表型。在 CD16 介导的抗体结合后，它们可以获得效应功能。这些研究结果表明，Treg 和 Tcon 细胞具有不常见的促炎症先天性样分化，并获得非特异性细胞毒性。这很可能是 CD 期间肠道炎症的原因和结果。
{"title":"Pro-inflammatory NK-like T cells are expanded in the blood and inflamed intestine in Crohn’s disease","authors":"Cristina M. Chiarolla , Axel R. Schulz , Michael Meir , Sebastian Ferrara , Yin Xiao , Simone Reu-Hofer , Addi J. Romero-Olmedo , Valeria Falcone , Katja Hoffmann , Maike Büttner-Herold , Martina Prelog , Andreas Rosenwald , Hartmut Hengel , Michael Lohoff , Hyun-Dong Chang , Nicolas Schlegel , Henrik E. Mei , 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<sup>+</sup> and CD8<sup>+</sup> T cells and a relative enrichment of CD4<sup>+</sup> regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4<sup>+</sup>FOXP3<sup>+</sup>HLA-DR<sup>+</sup>TIGIT<sup>–</sup> and CD4<sup>+</sup>FOXP3<sup>+</sup>CD56<sup>+</sup>, 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<sup>+</sup>CCR6<sup>+</sup>CD127<sup>+</sup> T cells appeared, being CD4<sup>+</sup> or CD8<sup>+</sup>, 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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.11.006
Mariela Artola-Borán , Lydia Kirsche , Angela Fallegger , Peter Leary , Mine Tanriover , Tanja Goodwin , Gavin Geiger , Siegfried Hapfelmeier , Shida Yousefi , Hans-Uwe Simon , Isabelle C. Arnold , Anne Müller
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 Helicobacter pylori and Citrobacter rodentium. 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 H. pylori, 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 C. rodentium in all examined tissues, suffer from more severe weight loss and develop more colitis. In contrast, H. pylori 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 H. pylori 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.
IgA 抗体在清除粘膜病原体方面发挥着重要作用。在这项研究中，我们考察了 IgA 对胃肠道细菌病原体幽门螺旋杆菌和枸橼酸杆菌的免疫控制作用。这两种细菌都会引发强烈的局部 IgA 反应，导致小鼠和胃炎患者的细菌 IgA 被覆。在这两种模型中，向 IgA 的类别转换取决于佩耶氏斑块、T 细胞、嗜酸性粒细胞和嗜酸性粒细胞衍生的 TGF-β。在幽门螺杆菌的情况下，IgA 的分泌和细菌包被也依赖于功能性细菌 IV 型分泌系统，该系统驱动 Th17 细胞的生成和依赖于 IL-17 的聚合免疫球蛋白受体 PIGR 的表达。IgA-/- 小鼠的所有受检组织中都有鼠疫杆菌的高定植率，体重减轻更严重，结肠炎发病率更高。相比之下，IgA-/-小鼠比 WT 小鼠更有效地控制幽门螺杆菌。WT养母提供的母体IgA可以弥补后代IgA缺乏的影响。我们把在IgA-/-小鼠身上观察到的免疫控制的改善归因于IgA介导的对补体杀伤的保护，因为幽门螺杆菌的定植在同时缺乏IgA和中心补体成分C3的复合品系中恢复到了野生型水平。因此，IgA 抗体可根据感染病原体的不同而具有保护性或有害性作用。
{"title":"IgA facilitates the persistence of the mucosal pathogen Helicobacter pylori","authors":"Mariela Artola-Borán , Lydia Kirsche , Angela Fallegger , Peter Leary , Mine Tanriover , Tanja Goodwin , Gavin Geiger , Siegfried Hapfelmeier , Shida Yousefi , Hans-Uwe Simon , Isabelle C. Arnold , 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<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>−/−</sup> 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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2025.01.012
Luke B Roberts, Alanna M Kelly, Matthew R Hepworth
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.
{"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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.09.002
Wan-Bing Dai , Xiao Zhang , Xu-Liang Jiang , Yi-Zhe Zhang , Ling-Ke Chen , Wei-Tian Tian , Xiao-Xin Zhou , Xiao-Yu Sun , Li-Li Huang , Xi-Yao Gu , Xue-Mei Chen , Xiao-Dan Wu , Jie Tian , Wei-Feng Yu , Lei Shen , Dian-San Su
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.
术后认知功能障碍（POCD）是一种常见的神经系统并发症，可在麻醉/手术后数天、数月甚至数年内影响学习和记忆。POCD 与肠道微生物群组成的改变（菌群失调）密切相关，但伴随而来的代谢变化及其在肠脑沟通和 POCD 发病机制中的作用仍不清楚。本研究报告了老年小鼠的麻醉/手术诱导肠道吲哚胺 2,3-二氧化酶（IDO）活性升高，从而使肠道色氨酸（TRP）代谢转向更多的 IDO 催化的犬尿氨酸（KYN）和更少的肠道细菌代谢的吲哚乙酸（IAA）。麻醉/手术和腹腔注射 KYN 都会引起 KYN 水平升高，而 KYN 水平升高与空间学习和记忆受损有关，而膳食中补充 IAA 则会减轻麻醉/手术引起的认知障碍。从机理上讲，麻醉/手术增加了小肠固有层中产生干扰素-γ（IFN-γ）的第1组先天性淋巴细胞（ILC1）的比例，并提高了肠道IDO的表达和活性，KYN与TRP的比例升高就表明了这一点。IDO抑制剂1-MT和针对IFN-γ或ILC的抗体可减轻麻醉/手术诱发的认知功能障碍，这表明肠道ILC1的扩张和随之而来的IFN-γ诱导的IDO上调可能是POCD向KYN途径转变的主要介导途径。肠道中的 ILC1-KYN 通路可能是治疗 POCD 的一个很有前景的靶点。
{"title":"The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction","authors":"Wan-Bing Dai , Xiao Zhang , Xu-Liang Jiang , Yi-Zhe Zhang , Ling-Ke Chen , Wei-Tian Tian , Xiao-Xin Zhou , Xiao-Yu Sun , Li-Li Huang , Xi-Yao Gu , Xue-Mei Chen , Xiao-Dan Wu , Jie Tian , Wei-Feng Yu , Lei Shen , 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}
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.
{"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":"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}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.11.007
Michael A. Schumacher , Megan H. Thai , Jonathan J. Hsieh , Alexa Gramajo , Cambrian Y. Liu , Mark R. Frey
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.
{"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 , Megan H. Thai , Jonathan J. Hsieh , Alexa Gramajo , Cambrian Y. Liu , 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}
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