Pub Date : 2025-12-01DOI: 10.1016/j.mucimm.2025.08.006
Faisal Nuhu , Marina Costa-Fujishima , Christina Gavino , Aloysious Ssemaganda , Melika Verdipanah , Naima Jahan , Thomas Murooka , Lyle R. McKinnon
Genital inflammation is associated with increased HIV risk. We previously found that endocervical Tregs correlated with decreased genital inflammation and reduced HIV target cells. IL-2 induces Tregs, and efforts to potentiate its regulatory activities clinically are ongoing. In this study, intraperitoneal administration of IL-2 conjugated to IL-2mAb clone JES6-1A12 (IL2C-trimeric) in estrous-synchronized female FoxP3GFP mice selectively expanded Tregs in the lower female genital tract, with limited effects on non-Treg cells. IL2C-trimeric increased the expression of GITR on Tregs, and most Tregs expressed tissue residency markers. IL2C-trimeric pre-treatment prevented neutrophil influx during vaginal challenge with both nonoxynol-9 (N-9) and Mobiluncus mulieris, but maintenance of E-cadherin expression and barrier integrity was only observed for M. mulieris and not N-9. Depletion of FoxP3+Tregs reversed the protective effects of IL2C-trimeric. Thus, induction of Tregs could be a potential strategy to regulate genital inflammation, reduce HIV acquisition risk, and improve reproductive health outcomes in women.
{"title":"Expansion of genital Tregs reduces neutrophil influx and maintains mucosal barrier integrity during inflammatory bacteria challenge","authors":"Faisal Nuhu , Marina Costa-Fujishima , Christina Gavino , Aloysious Ssemaganda , Melika Verdipanah , Naima Jahan , Thomas Murooka , Lyle R. McKinnon","doi":"10.1016/j.mucimm.2025.08.006","DOIUrl":"10.1016/j.mucimm.2025.08.006","url":null,"abstract":"<div><div>Genital inflammation is associated with increased HIV risk. We previously found that endocervical Tregs correlated with decreased genital inflammation and reduced HIV target cells. IL-2 induces Tregs, and efforts to potentiate its regulatory activities clinically are ongoing. In this study, intraperitoneal administration of IL-2 conjugated to IL-2mAb clone JES6-1A12 (IL2C-trimeric) in estrous-synchronized female FoxP3<sup>GFP</sup> mice selectively expanded Tregs in the lower female genital tract, with limited effects on non-Treg cells. IL2C-trimeric increased the expression of GITR on Tregs, and most Tregs expressed tissue residency markers. IL2C-trimeric pre-treatment prevented neutrophil influx during vaginal challenge with both nonoxynol-9 (N-9) and <em>Mobiluncus mulieris</em>, but maintenance of E-cadherin expression and barrier integrity was only observed for <em>M. mulieris</em> and not N-9. Depletion of FoxP3<sup>+</sup>Tregs reversed the protective effects of IL2C-trimeric. Thus, induction of Tregs could be a potential strategy to regulate genital inflammation, reduce HIV acquisition risk, and improve reproductive health outcomes in women.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1298-1312"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961829","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.10.006
Samuel Alvarez-Arguedas , Khadijah Mazhar , Andi Wangzhou , Ishwarya Sankaranarayanan , Gabriela Gaona , John T. Lafin , Ron B. Mitchell , Theodore J. Price , Michael U. Shiloh
{"title":"Erratum to “Single cell transcriptional analysis of human adenoids identifies molecular features of airway microfold cells”. [Mucosal Immunol. 18(5) (2025) 1199–1217]","authors":"Samuel Alvarez-Arguedas , Khadijah Mazhar , Andi Wangzhou , Ishwarya Sankaranarayanan , Gabriela Gaona , John T. Lafin , Ron B. Mitchell , Theodore J. Price , Michael U. Shiloh","doi":"10.1016/j.mucimm.2025.10.006","DOIUrl":"10.1016/j.mucimm.2025.10.006","url":null,"abstract":"","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Page 1462"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346225","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.08.007
Saifei Wang, Bohan Qi, Chunyu Du, Peng Ma, Yao Zhang, Shuxin Chen, E Tian, Hansong Deng
Bacterial membrane vesicles (MVs) are critical mediators of virulence factor delivery and intercellular communication, yet the mechanisms by which hosts detect and respond to these vesicles remain poorly characterized. Through transcriptional profiling, we found that MVs derived from the non-lethal pathogenic Erwinia carotovora carotovora 15 (Ecc15) robustly induce reactive oxygen species (ROS) production and systemically upregulate Jon genes—a family of immune-related genes—in the Drosophila intestine 24 h post-infection. Strikingly, these effects contrast with transcriptional changes observed upon gut-specific overexpression of CRTC, the coactivator of the conserved transcription factor cAMP response element-binding protein (CREB). Intriguingly, ingestion of OMVs from Ecc15 or from the Gram-positive bacterium Lactobacillus plantarum (L.plantarum) significantly suppresses CREB activity in enterocytes (ECs). Fractionation experiments revealed that proteinaceous components within bacterial MVs inhibited CREB activity by reducing apical Ca2+ levels in ECs. Mechanistically, the CRTC/CREB cascade promoted gut microbial load by transcriptionally repressing PGRP-SC2-dependent amidase activity, a pathway independent of the canonical Relish/Imd signaling axis. Furthermore, OMVs from E. coli (BL21) also potently suppressed expression of pro-inflammatory factors, such as IL-6 and CXCL10 in NIH3T3 by blocking the activity of CREB. Collectively, these findings demonstrated that CREB play a conserved role on sense bacterial MVs and trigger anti-infection defenses in both Drosophila and mammalian systems, unveiling a novel paradigm in host-microbe communication.
{"title":"CREB-mediated sensing of bacterial membrane vesicles unveils a conserved host defense pathway","authors":"Saifei Wang, Bohan Qi, Chunyu Du, Peng Ma, Yao Zhang, Shuxin Chen, E Tian, Hansong Deng","doi":"10.1016/j.mucimm.2025.08.007","DOIUrl":"10.1016/j.mucimm.2025.08.007","url":null,"abstract":"<div><div>Bacterial membrane vesicles (MVs) are critical mediators of virulence factor delivery and intercellular communication, yet the mechanisms by which hosts detect and respond to these vesicles remain poorly characterized. Through transcriptional profiling, we found that MVs derived from the non-lethal pathogenic <em>Erwinia carotovora carotovora 15 (Ecc15)</em> robustly induce reactive oxygen species (ROS) production and systemically upregulate Jon genes—a family of immune-related genes—in the Drosophila intestine 24 h post-infection. Strikingly, these effects contrast with transcriptional changes observed upon gut-specific overexpression of CRTC, the coactivator of the conserved transcription factor cAMP response element-binding protein (CREB). Intriguingly, ingestion of OMVs from <em>Ecc15</em> or from the Gram-positive bacterium <em>Lactobacillus plantarum (L.plantarum)</em> significantly suppresses CREB activity in enterocytes (ECs). Fractionation experiments revealed that proteinaceous components within bacterial MVs inhibited CREB activity by reducing apical Ca<sup>2+</sup> levels in ECs. Mechanistically, the CRTC/CREB cascade promoted gut microbial load by transcriptionally repressing PGRP-SC2-dependent amidase activity, a pathway independent of the canonical Relish/Imd signaling axis. Furthermore, OMVs from <em>E. coli (BL21)</em> also potently suppressed expression of pro-inflammatory factors, such as IL-6 and CXCL10 in NIH3T3 by blocking the activity of CREB. Collectively, these findings demonstrated that CREB play a conserved role on sense bacterial MVs and trigger anti-infection defenses in both Drosophila and mammalian systems, unveiling a novel paradigm in host-microbe communication.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1313-1324"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961696","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.08.002
Lauren E. Springer , Han-Zhi Rao , Oliver Abinader , Ramkrishna Mitra , Christopher M. Snyder
Lipid mediators play important, yet poorly understood roles in regulating immune responses. Cytomegalovirus (CMV) is a herpesvirus that persists in mucosal tissues. Prior work suggests that leukotrienes, a class of inflammatory lipid mediators, contribute to viral control. Infection with murine (M)CMV altered leukotriene and other lipid mediator production in the nasal mucosa, lungs and salivary glands of mice. Mice lacking the receptor for leukotriene B4 (BLT1−/−) had increased viral titers at early timepoints in the nasal mucosa and lungs and produced less interferon (IFN)-γ in both tissues, altering the balance between IFN-γ and interleukin (IL)-10. Importantly, viral control in BLT1−/− mice was restored by IL-10 blockade, showing that leukotriene B4 promotes an optimal IFN-γ/IL-10 balance in these mucosal sites during acute infection. BLT1−/− T cells showed no defects in the ability to produce IFN-γ, but their gene expression profiles suggested reduced activation and altered migratory capacity. MCMV-specific T cells compete for access to infected cells. Remarkably, when in competition with wild-type T cells, BLT1−/− T cells competed poorly for antigen, resulting in reduced expansion. These data suggest that leukotriene B4 promotes control of CMV by optimizing T cell encounters with infected targets, maintaining the balance between IFN-γ and IL-10.
{"title":"Leukotriene B4 regulates T cell recognition and control of MCMV in mucosal tissues","authors":"Lauren E. Springer , Han-Zhi Rao , Oliver Abinader , Ramkrishna Mitra , Christopher M. Snyder","doi":"10.1016/j.mucimm.2025.08.002","DOIUrl":"10.1016/j.mucimm.2025.08.002","url":null,"abstract":"<div><div>Lipid mediators play important, yet poorly understood roles in regulating immune responses. Cytomegalovirus (CMV) is a herpesvirus that persists in mucosal tissues. Prior work suggests that leukotrienes, a class of inflammatory lipid mediators, contribute to viral control. Infection with murine (M)CMV altered leukotriene and other lipid mediator production in the nasal mucosa, lungs and salivary glands of mice. Mice lacking the receptor for leukotriene B4 (BLT1<sup>−/−</sup>) had increased viral titers at early timepoints in the nasal mucosa and lungs and produced less interferon (IFN)-γ in both tissues, altering the balance between IFN-γ and interleukin (IL)-10. Importantly, viral control in BLT1<sup>−/−</sup> mice was restored by IL-10 blockade, showing that leukotriene B4 promotes an optimal IFN-γ/IL-10 balance in these mucosal sites during acute infection. BLT1<sup>−/−</sup> T cells showed no defects in the ability to produce IFN-γ, but their gene expression profiles suggested reduced activation and altered migratory capacity. MCMV-specific T cells compete for access to infected cells. Remarkably, when in competition with wild-type T cells, BLT1<sup>−/−</sup> T cells competed poorly for antigen, resulting in reduced expansion. These data suggest that leukotriene B4 promotes control of CMV by optimizing T cell encounters with infected targets, maintaining the balance between IFN-γ and IL-10.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1240-1256"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961882","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.09.002
Yiran Li , Shilpi Singh , Hannah L. Briggs , Jordan E. Kreger , Alex L. Sliwicki , Emily L. Eberhardt , Shiuhyang Kuo , Jessica A. Czapla , J. Kelley Bentley , Heidi R. Flori , Amjad Horani , Steven L. Brody , Marc B. Hershenson
Despite recognition of rhinovirus-C (RV-C) as a cause of severe respiratory exacerbations, little is known about the pathogenesis of RV-C infections. We infected mucociliary-differentiated primary tracheobronchial epithelial cells with RV-C15 or RV-A16. Initial RNASeq data showed that, compared to RV-A16, RV-C15 decreased expression of genes related to ciliary function while increasing expression of genes associated with mucus secretion and inflammation. Using different airway epithelial cell isolates, we confirmed greater reduction in DNAI2 and FOXJ1 (regulates production of motile cilia) and increased FOXA3 (regulates mucin −related gene expression) after RV-C15 infection compared to RV-A16. Similarly, nasal swab samples from children with RV-C but not RV-A infections showed significantly decreased DNAI2 and FOXJ1 mRNA compared to controls. While both RV-C15 and RV-A16 infection of airway epithelial cells increased mRNA expression and secretion of MUC5AC, RV-C15 induced greater airway surface liquid thickness, as measured by FITC-dextran staining. DAPT, a Notch inhibitor, reversed the effects of RV-C15 on DNAI2, FOXJ1 and FOXA3 expression. RV-C15 induced loss of α-acetyl tubulin, extrusion of airway epithelial cells, dissociation of ZO-1 from tight junctions, reduced ciliary beat frequency and decreased epithelial cell transepithelial electrical resistance. Finally, protein abundance of pro-inflammatory cytokines in cell supernatants and nasal samples also tended to be higher after RV-C infection. We conclude that RV-C causes significant disruptions in airway epithelial cell ciliary function which may lead to airway obstruction. Such disruptions may play a role in the severity of RV-C respiratory tract infections.
尽管人们认识到鼻病毒- c （RV-C）是严重呼吸系统恶化的原因，但对RV-C感染的发病机制知之甚少。我们用RV-C15或RV-A16感染粘膜纤毛分化的原代气管支气管上皮细胞。初始RNASeq数据显示，与RV-A16相比，RV-C15减少了纤毛功能相关基因的表达，而增加了粘液分泌和炎症相关基因的表达。使用不同的气道上皮细胞分离物，我们证实，与RV-A16相比，RV-C15感染后DNAI2和FOXJ1（调节运动性纤毛的产生）的减少更大，FOXA3（调节粘蛋白相关基因表达）的增加更大。同样，与对照组相比，感染RV-C但未感染RV-A的儿童的鼻拭子样本显示DNAI2和FOXJ1 mRNA显著降低。通过fitc -葡聚糖染色检测，虽然RV-C15和RV-A16感染气道上皮细胞均增加mRNA表达和MUC5AC分泌，但RV-C15诱导气道表面液体厚度增加。Notch抑制剂DAPT逆转了RV-C15对DNAI2、FOXJ1和FOXA3表达的影响。RV-C15诱导α-乙酰基小管蛋白缺失，气道上皮细胞挤压，ZO-1与紧密连接分离，睫状搏动频率降低，上皮细胞经上皮电阻降低。最后，病毒感染后，细胞上清液和鼻腔样本中促炎细胞因子的蛋白丰度也趋于较高。我们得出结论，RV-C引起气道上皮细胞纤毛功能的显著破坏，这可能导致气道阻塞。这种破坏可能在RV-C呼吸道感染的严重程度中发挥作用。
{"title":"Rhinovirus C15 infection induces airway epithelial cell remodeling and robust inflammatory responses: Potential implications for airway obstruction in children","authors":"Yiran Li , Shilpi Singh , Hannah L. Briggs , Jordan E. Kreger , Alex L. Sliwicki , Emily L. Eberhardt , Shiuhyang Kuo , Jessica A. Czapla , J. Kelley Bentley , Heidi R. Flori , Amjad Horani , Steven L. Brody , Marc B. Hershenson","doi":"10.1016/j.mucimm.2025.09.002","DOIUrl":"10.1016/j.mucimm.2025.09.002","url":null,"abstract":"<div><div>Despite recognition of rhinovirus-C (RV-C) as a cause of severe respiratory exacerbations, little is known about the pathogenesis of RV-C infections. We infected mucociliary-differentiated primary tracheobronchial epithelial cells with RV-C15 or RV-A16. Initial RNASeq data showed that, compared to RV-A16, RV-C15 decreased expression of genes related to ciliary function while increasing expression of genes associated with mucus secretion and inflammation. Using different airway epithelial cell isolates, we confirmed greater reduction in <em>DNAI2</em> and <em>FOXJ1</em> (regulates production of motile cilia) and increased <em>FOXA3</em> (regulates mucin −related gene expression) after RV-C15 infection compared to RV-A16. Similarly, nasal swab samples from children with RV-C but not RV-A infections showed significantly decreased <em>DNAI2</em> and <em>FOXJ1</em> mRNA compared to controls. While both RV-C15 and RV-A16 infection of airway epithelial cells increased mRNA expression and secretion of MUC5AC, RV-C15 induced greater airway surface liquid thickness, as measured by FITC-dextran staining. DAPT, a Notch inhibitor, reversed the effects of RV-C15 on <em>DNAI2, FOXJ1</em> and <em>FOXA3</em> expression. RV-C15 induced loss of α-acetyl tubulin, extrusion of airway epithelial cells, dissociation of ZO-1 from tight junctions, reduced ciliary beat frequency and decreased epithelial cell transepithelial electrical resistance. Finally, protein abundance of pro-inflammatory cytokines in cell supernatants and nasal samples also tended to be higher after RV-C infection. We conclude that RV-C causes significant disruptions in airway epithelial cell ciliary function which may lead to airway obstruction. Such disruptions may play a role in the severity of RV-C respiratory tract infections.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1341-1352"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102837","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}
Mucosal IgA antibodies are the first defence against mucosal infections. Besides targeting specific antigens by their Fab-region, IgA also mediates antiviral functions via their Fc-domain, allowing infected cells destruction by antibody-dependent cellular phagocytosis (ADCP). Passive immunisation with anti-HIV-1 IgG protected Non-Human Primates in a CD8+ T cell-dependent manner, a process likely involving ADCP. Here, we unravel the consequences of ADCP of HIV-1-infected cells mediated by anti-HIV envelope IgA compared to IgG. We found that IgA-mediated ADCP, not IgG, drives viral antigen cross-presentation to HIV-1-specific cytotoxic CD8+ T cells. IgA effector function reprogrammed ADCP effector monocytes into activated macrophages exhibiting a mixed pro- and anti-inflammatory profile combined with increased pro-inflammatory chemokines. IgA-mediated ADCP sensitizes monocytes to respond to a novel bacterial challenge by secreting IL-6 and TNFα, indicative of acquired trained immunity. Altogether, these data establish a bridge between humoral and cellular immunity that could be exploited in HIV preventive strategies.
{"title":"IgA-dependent cell phagocytosis of HIV-infected cells elicits cross-presentation to CD8+T cells and immune memory in effector monocytes","authors":"Andrea Cottignies-Calamarte , Annouk Dauvilliers , Lucie Adoux , Benjamin Saint-Pierre , Franck Letourneur , Sylvain Cardinaud , Daniela Tudor , Morgane Bomsel","doi":"10.1016/j.mucimm.2025.09.004","DOIUrl":"10.1016/j.mucimm.2025.09.004","url":null,"abstract":"<div><div>Mucosal IgA antibodies are the first defence against mucosal infections. Besides targeting specific antigens by their Fab-region, IgA also mediates antiviral functions via their Fc-domain, allowing infected cells destruction by antibody-dependent cellular phagocytosis (ADCP). Passive immunisation with anti-HIV-1 IgG protected Non-Human Primates in a CD8<sup>+</sup> T cell-dependent manner, a process likely involving ADCP. Here, we unravel the consequences of ADCP of HIV-1-infected cells mediated by anti-HIV envelope IgA compared to IgG. We found that IgA-mediated ADCP, not IgG, drives viral antigen cross-presentation to HIV-1-specific cytotoxic CD8<sup>+</sup> T cells. IgA effector function reprogrammed ADCP effector monocytes into activated macrophages exhibiting a mixed pro- and anti-inflammatory profile combined with increased pro-inflammatory chemokines. IgA-mediated ADCP sensitizes monocytes to respond to a novel bacterial challenge by secreting IL-6 and TNFα, indicative of acquired trained immunity. Altogether, these data establish a bridge between humoral and cellular immunity that could be exploited in HIV preventive strategies.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1366-1380"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102839","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.08.003
Matthias Kelm , Natalie Burkard , Marius Hörner , Catherine Kollmann , Christoph Otto , Babak Saravi , Anna C. Seubert , Friedrich Forchel , Timo N. Kohler , Matthew Penner , Florian Hollfelder , Stefanie Schmidt , Brenda Gerull , Rebecca Springer , Stefanie Kampmeier , Vera Rauschenberger , Nikita Deoghare , Christoph-Thomas Germer , Panagiota Arampatzi , Daniela Kugelmann , Nicolas Schlegel
Desmosomes play an underexplored role in intestinal homeostasis and are linked to the pathogenesis of inflammatory bowel diseases. We found a novel function of the desmosomal plaque protein Plakoglobin (JUP) in initiating the innate immune response to facilitate intestinal inflammation.
Tissue samples from Crohn’s disease (CD) patients revealed a loss of JUP, which was mirrored in a mouse model of dextran sodium sulfate-induced (DSS) colitis. Inducible intestinal epithelial-specific knock-out of Jup (iVilCreERT2Jupfl/fl) in mice resulted in increased submucosal infiltration of macrophages and neutrophils, along with activation of the inflammasome. This was paralleled by p38MAPK phosphorylation while loss intestinal epithelial barrier function was absent. In DSS-colitis, epithelial Jup-deficiency impaired recovery and enhanced IL23/IL17-signaling. Intestinal organoids lacking Jup demonstrated NLRP1 inflammasome activation, indicated by increased IL1β and IL18 levels, which was attenuated by p38MAPK inhibition. In silico analysis and co-immunoprecipitation confirmed a direct interaction between JUP and p38MAPK, revealing a regulatory mechanism where JUP limits inflammasome signaling in intestinal epithelial cells. These effects were blunted by NLRP1/3 inhibitor ADS032..
These findings identify JUP as a critical modulator of epithelial innate immunity in the gut. The loss of JUP in tissues from CD patients underscores its potential relevance in disease pathology.
{"title":"Junctional epithelial Plakoglobin facilitates intestinal inflammation by p38MAPK-dependent activation of the inflammasome","authors":"Matthias Kelm , Natalie Burkard , Marius Hörner , Catherine Kollmann , Christoph Otto , Babak Saravi , Anna C. Seubert , Friedrich Forchel , Timo N. Kohler , Matthew Penner , Florian Hollfelder , Stefanie Schmidt , Brenda Gerull , Rebecca Springer , Stefanie Kampmeier , Vera Rauschenberger , Nikita Deoghare , Christoph-Thomas Germer , Panagiota Arampatzi , Daniela Kugelmann , Nicolas Schlegel","doi":"10.1016/j.mucimm.2025.08.003","DOIUrl":"10.1016/j.mucimm.2025.08.003","url":null,"abstract":"<div><div>Desmosomes play an underexplored role in intestinal homeostasis and are linked to the pathogenesis of inflammatory bowel diseases. We found a novel function of the desmosomal plaque protein Plakoglobin (JUP) in initiating the innate immune response to facilitate intestinal inflammation.</div><div>Tissue samples from Crohn’s disease (CD) patients revealed a loss of JUP, which was mirrored in a mouse model of dextran sodium sulfate-induced (DSS) colitis. Inducible intestinal epithelial-specific knock-out of <em>Jup</em> (iVilCreER<sup>T2</sup><em>Jup</em><sup>fl/fl</sup>) in mice resulted in increased submucosal infiltration of macrophages and neutrophils, along with activation of the inflammasome. This was paralleled by p38MAPK phosphorylation while loss intestinal epithelial barrier function was absent. In DSS-colitis, epithelial <em>Jup</em>-deficiency impaired recovery and enhanced IL23/IL17-signaling. Intestinal organoids lacking <em>Jup</em> demonstrated NLRP1 inflammasome activation, indicated by increased IL1β and IL18 levels, which was attenuated by p38MAPK inhibition. <em>In silico</em> analysis and co-immunoprecipitation confirmed a direct interaction between JUP and p38MAPK, revealing a regulatory mechanism where JUP limits inflammasome signaling in intestinal epithelial cells. These effects were blunted by NLRP1/3 inhibitor ADS032..</div><div>These findings identify JUP as a critical modulator of epithelial innate immunity in the gut. The loss of JUP in tissues from CD patients underscores its potential relevance in disease pathology.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1257-1270"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859370","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.10.004
S.L. Tai , F. Wong , K. Burrows , L. Ngai , P. Chiaranunt , L. Savo , M. Jeong , Z.Y. Chen , L. Hao , F. Lau , J. Wang , A. Mortha
Group 3 innate lymphoid cells (ILC3) are tissue-resident lymphocytes that contribute to tissue and immune homeostasis. Alterations in ILC3 development or deficiency in their effector functions have beneficial and detrimental outcomes on chronic inflammation, host defense and barrier integrity. Although research has progressed in understanding these cells, multiple aspects of their biology remain poorly understood and difficult to investigate using current available techniques. This is primarily due to the lack of accessible and suitable tools to isolate, manipulate, and investigate ILC3 in vitro and in vivo. Here, we report an economical system to investigate the biology of ILC3 in vitro and in vivo, using the previously described ILC3 cell line MNK3. We demonstrate that MNK3 cells are a relevant model for in vivo investigations into the biology of ILC3. We describe and validate a straightforward strategy to genetically modify MNK3 cells ex vivo to dissect the role of their effector functions in the steady state or during inflammation and infection. Using this system, we identified a previously underappreciated role for ILC3-derived Colony Stimulating Factor 2 (CSF2) in regulating splenic and hepatic myeloid cell homeostasis. Collectively, we present a system to investigate the biology of ILC3 that is suitable, and accessible to a wider audience in academic research.
{"title":"Group 3 innate lymphoid cell-derived CSF2 tunes homeostasis of tissue macrophages and neutrophils","authors":"S.L. Tai , F. Wong , K. Burrows , L. Ngai , P. Chiaranunt , L. Savo , M. Jeong , Z.Y. Chen , L. Hao , F. Lau , J. Wang , A. Mortha","doi":"10.1016/j.mucimm.2025.10.004","DOIUrl":"10.1016/j.mucimm.2025.10.004","url":null,"abstract":"<div><div>Group 3 innate lymphoid cells (ILC3) are tissue-resident lymphocytes that contribute to tissue and immune homeostasis. Alterations in ILC3 development or deficiency in their effector functions have beneficial and detrimental outcomes on chronic inflammation, host defense and barrier integrity. Although research has progressed in understanding these cells, multiple aspects of their biology remain poorly understood and difficult to investigate using current available techniques. This is primarily due to the lack of accessible and suitable tools to isolate, manipulate, and investigate ILC3 <em>in vitro</em> and <em>in vivo</em>. Here, we report an economical system to investigate the biology of ILC3 <em>in vitro</em> and <em>in vivo</em>, using the previously described ILC3 cell line MNK3. We demonstrate that MNK3 cells are a relevant model for <em>in vivo</em> investigations into the biology of ILC3. We describe and validate a straightforward strategy to genetically modify MNK3 cells <em>ex vivo</em> to dissect the role of their effector functions in the steady state or during inflammation and infection. Using this system, we identified a previously underappreciated role for ILC3-derived Colony Stimulating Factor 2 (CSF2) in regulating splenic and hepatic myeloid cell homeostasis. Collectively, we present a system to investigate the biology of ILC3 that is suitable, and accessible to a wider audience in academic research.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1450-1461"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258490","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.09.005
Abdulhadi Suwandi , Soeren Ocvirk , Alibek Galeev , Marijana Basic , Reza R.A. Naderi , Daphne Dior Tientcheu Tchokoafi , Anika Sander , Christiane Ring , Diana Ring , Gopala Nishanth , Katrin Künnemann , Dirk Schlüter , Andre Bleich , Michael Blaut , Bärbel Stecher , Gunnar Loh , Guntram A. Grassl
Salmonella enterica serovar Typhimurium is a food-borne pathogen and a major cause of gastroenteritis in humans. The intestinal microbiota provides colonization resistance to enteric pathogens such as S. Typhimurium. Akkermansia muciniphila is an anaerobic bacterium commonly found in the intestinal tract of humans and other mammals and specializes in the degradation of mucin. To study the role of A. muciniphila in affecting the outcome of S. Typhimurium colonization and pathology, we used gnotobiotic mice colonized with a defined simplified human (SIHUMI) or mouse (OMM11) intestinal microbiota and infected them with the attenuated S. Typhimurium ΔaroA strain. By comparing SIHUMI and OMM11 mice to mice additionally colonized with A. muciniphila, we demonstrate that the presence of A. muciniphila leads to a decrease in intestinal Salmonella colonization. In addition, Salmonella-induced colitis is significantly reduced in the presence of A. muciniphila including improved histopathological changes as well as decreased levels of inflammatory cytokines. Furthermore, we demonstrate that viable A. muciniphila inhibit adhesion of Salmonella to the intestinal epithelium in vivo as well as to differentiated, polarized HT29-MTX-E12 epithelial cells. These data indicate that A. muciniphila plays an important role in mediating protection from S. Typhimurium colitis by inhibiting adhesion of Salmonella to the intestinal epithelium.
{"title":"Akkermansia muciniphila ameliorates Salmonella-induced colitis and intestinal fibrosis","authors":"Abdulhadi Suwandi , Soeren Ocvirk , Alibek Galeev , Marijana Basic , Reza R.A. Naderi , Daphne Dior Tientcheu Tchokoafi , Anika Sander , Christiane Ring , Diana Ring , Gopala Nishanth , Katrin Künnemann , Dirk Schlüter , Andre Bleich , Michael Blaut , Bärbel Stecher , Gunnar Loh , Guntram A. Grassl","doi":"10.1016/j.mucimm.2025.09.005","DOIUrl":"10.1016/j.mucimm.2025.09.005","url":null,"abstract":"<div><div><em>Salmonella enterica</em> serovar Typhimurium is a food-borne pathogen and a major cause of gastroenteritis in humans. The intestinal microbiota provides colonization resistance to enteric pathogens such as <em>S.</em> Typhimurium. <em>Akkermansia muciniphila</em> is an anaerobic bacterium commonly found in the intestinal tract of humans and other mammals and specializes in the degradation of mucin. To study the role of <em>A. muciniphila</em> in affecting the outcome of <em>S.</em> Typhimurium colonization and pathology, we used gnotobiotic mice colonized with a defined simplified human (SIHUMI) or mouse (OMM<sup>11</sup>) intestinal microbiota and infected them with the attenuated <em>S.</em> Typhimurium Δ<em>aroA</em> strain. By comparing SIHUMI and OMM<sup>11</sup> mice to mice additionally colonized with <em>A. muciniphila</em>, we demonstrate that the presence of <em>A. muciniphila</em> leads to a decrease in intestinal <em>Salmonella</em> colonization. In addition, <em>Salmonella</em>-induced colitis is significantly reduced in the presence of <em>A. muciniphila</em> including improved histopathological changes as well as decreased levels of inflammatory cytokines. Furthermore, we demonstrate that viable <em>A. muciniphila</em> inhibit adhesion of <em>Salmonella</em> to the intestinal epithelium <em>in vivo</em> as well as to differentiated, polarized HT29-MTX-E12 epithelial cells. These data indicate that <em>A. muciniphila</em> plays an important role in mediating protection from <em>S.</em> Typhimurium colitis by inhibiting adhesion of <em>Salmonella</em> to the intestinal epithelium.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1381-1393"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081159","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 : 2025-12-01DOI: 10.1016/j.mucimm.2025.09.007
Chunyang Tian , Xiaoqi Ye , Shanshan Xiong , Gayatree Mohapatra , Sinan Lin , Ziyin Ye , Siyun Huang , Xin Yu , Baili Chen , Yao He , Yinglian Xiao , Zhirong Zeng , Yijun Zhu , Minhu Chen , Danping Zheng
Monogenic errors of immunity can present with inflammatory bowel disease (IBD)-like enteropathy. We describe an adolescent with IBD- and Behçet’s-like phenotype, resulting from an intronic, loss of function mutation (c.248-7G > A) in ELF4, an X-linked transcription factor executing multiple biological functions. The mutation causes abnormal splicing and decreased mRNA expression and impairs ELF4 protein expression in the blood and colon. Functionally, the mutation results in loss of ELF4 transcriptional activity, and transcriptionally induces auto-inflammatory responses in the patient’s peripheral blood mononuclear cells, which promote secretion of the pro-inflammatory cytokine interleukin-6 upon lipopolysaccharide stimulation. Single-cell transcriptional profiling of inflamed colonic biopsy specimens from the patient delineates a comprehensive landscape of mucosal innate and adaptive immune dysregulation. This analysis not only uncovers inflammatory signatures reminiscent of Crohn’s disease but also demonstrates heightened angiogenic chemokine responses and enhanced chemotactic activity in innate immune cells. These results demonstrate that a new ELF4 loss-of-function intronic mutation predisposes to an intestinal autoinflammatory disorder.
{"title":"Novel loss-of-function intronic mutation in ELF4 is associated with intestinal autoinflammation","authors":"Chunyang Tian , Xiaoqi Ye , Shanshan Xiong , Gayatree Mohapatra , Sinan Lin , Ziyin Ye , Siyun Huang , Xin Yu , Baili Chen , Yao He , Yinglian Xiao , Zhirong Zeng , Yijun Zhu , Minhu Chen , Danping Zheng","doi":"10.1016/j.mucimm.2025.09.007","DOIUrl":"10.1016/j.mucimm.2025.09.007","url":null,"abstract":"<div><div>Monogenic errors of immunity can present with inflammatory bowel disease (IBD)-like enteropathy. We describe an adolescent with IBD- and Behçet’s-like phenotype, resulting from an intronic, loss of function mutation (c.248-7G > A) in <em>ELF4</em>, an X-linked transcription factor executing multiple biological functions. The mutation causes abnormal splicing and decreased mRNA expression and impairs ELF4 protein expression in the blood and colon. Functionally, the mutation results in loss of <em>ELF4</em> transcriptional activity, and transcriptionally induces auto-inflammatory responses in the patient’s peripheral blood mononuclear cells, which promote secretion of the pro-inflammatory cytokine interleukin-6 upon lipopolysaccharide stimulation. Single-cell transcriptional profiling of inflamed colonic biopsy specimens from the patient delineates a comprehensive landscape of mucosal innate and adaptive immune dysregulation. This analysis not only uncovers inflammatory signatures reminiscent of Crohn’s disease but also demonstrates heightened angiogenic chemokine responses and enhanced chemotactic activity in innate immune cells. These results demonstrate that a new <em>ELF4</em> loss-of-function intronic mutation predisposes to an intestinal autoinflammatory disorder.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1394-1404"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176042","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}
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