Mucosal Immunology最新文献

{"title":"Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections","authors":"Israel Cotzomi-Ortega ,&nbsp;Emily E. Rosowski ,&nbsp;Xin Wang ,&nbsp;Yuriko I. Sanchez-Zamora ,&nbsp;Jeimy M. Lopez-Torres ,&nbsp;Gamaliel Sanchez-Orellana ,&nbsp;Rachel Han ,&nbsp;Gabriela Vásquez-Martínez ,&nbsp;Gabriel Mayoral Andrade ,&nbsp;Gregory Ballash ,&nbsp;Hanna Cortado ,&nbsp;Birong Li ,&nbsp;Yusuf Ali ,&nbsp;Raul Rascon ,&nbsp;Frank Robledo-Avila ,&nbsp;Santiago Partida-Sanchez ,&nbsp;Eduardo Pérez-Campos ,&nbsp;Peter Olofsson-Sahl ,&nbsp;Diana Zepeda-Orozco ,&nbsp;John David Spencer ,&nbsp;Juan de Dios Ruiz-Rosado","doi":"10.1016/j.mucimm.2024.12.010","DOIUrl":"10.1016/j.mucimm.2024.12.010","url":null,"abstract":"<div><div>The precise role of neutrophil-derived reactive oxygen species (ROS) in combating bacterial uropathogens during urinary tract infections (UTI) remains largely unexplored. In this study, we elucidate the antimicrobial significance of NADPH oxidase 2 (NOX2)-derived ROS, as opposed to mitochondrial ROS, in facilitating neutrophil-mediated eradication of uropathogenic <em>Escherichia coli</em> (UPEC), the primary causative agent of UTI. Furthermore, NOX2-derived ROS regulate NF-κB-mediated inflammatory responses in neutrophils against UPEC by inducing the release of nuclear factor erythroid 2-related factor 2 (Nrf2) from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Consistently, the absence of NOX2 (<em>Cybb^-/-</em>) in mice led to uncontrolled bacterial infection associated with increased NF-κB signaling, heightened neutrophilic inflammation, and increased bladder pathology during cystitis. These findings underscore a dual role for neutrophil NOX2 in both eradicating UPEC and mitigating neutrophil-mediated inflammation in the urinary tract, revealing a previously unrecognized effector and regulatory mechanism in the control of UTI.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 402-417"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877543","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":"Impact of smoking on gut microbiota and short-chain fatty acids in human and mice: Implications for COPD","authors":"Shiro Otake ,&nbsp;Shotaro Chubachi ,&nbsp;Junki Miyamoto ,&nbsp;Yuri Haneishi ,&nbsp;Tetsuya Arai ,&nbsp;Hideto Iizuka ,&nbsp;Takashi Shimada ,&nbsp;Kaori Sakurai ,&nbsp;Shinichi Okuzumi ,&nbsp;Hiroki Kabata ,&nbsp;Takanori Asakura ,&nbsp;Jun Miyata ,&nbsp;Junichiro Irie ,&nbsp;Koichiro Asano ,&nbsp;Hidetoshi Nakamura ,&nbsp;Ikuo Kimura ,&nbsp;Koichi Fukunaga","doi":"10.1016/j.mucimm.2024.12.006","DOIUrl":"10.1016/j.mucimm.2024.12.006","url":null,"abstract":"<div><div>We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 353-365"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829355","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":"Breast milk delivery of an engineered dimeric IgA protects neonates against rotavirus","authors":"Stephanie N. Langel ,&nbsp;Claire E. Otero ,&nbsp;Justin T. Steppe ,&nbsp;Caitlin A. Williams ,&nbsp;Tatiana Travieso ,&nbsp;Jerry Chang ,&nbsp;Helen Webster ,&nbsp;Lauren E. Williamson ,&nbsp;James E. Crowe Jr ,&nbsp;Harry B. Greenberg ,&nbsp;Huali Wu ,&nbsp;Christoph P. Hornik ,&nbsp;Katayoun Mansouri ,&nbsp;Robert J. Edwards ,&nbsp;Victoria Stalls ,&nbsp;Priyamvada Acharya ,&nbsp;Maria Blasi ,&nbsp;Sallie R. Permar","doi":"10.1016/j.mucimm.2025.01.002","DOIUrl":"10.1016/j.mucimm.2025.01.002","url":null,"abstract":"<div><div>Dimeric IgA (dIgA) is the dominant antibody in many mucosal tissues. It is actively transported onto mucosal surfaces as secretory IgA (sIgA) which plays an integral role in protection against enteric pathogens, particularly in young children. Therapeutic strategies that deliver engineered, potently neutralizing antibodies directly into the infant intestine through breast milk could provide enhanced antimicrobial protection for neonates. Here, we developed a murine model of maternal protective transfer against human rotavirus (RV) using systemic administration of a dimeric IgA monoclonal antibody (mAb). First, we showed that systemically administered dIgA passively transferred into breast milk and the stomach of suckling pups in a dose-dependent manner. Next, we optimized the recombinant production of a potently RV-neutralizing, VP4-specific dIgA (mAb41) antibody. We then demonstrated that systemic administration of dIgA and IgG mAb41 in lactating dams conferred protection from RV-induced diarrhea in suckling pups, with dIgA resulting in lower diarrhea incidence from IgG. Systemic delivery of engineered antimicrobial dIgA mAbs should be considered as an effective strategy for sIgA delivery to the infant gastrointestinal tract via breast milk to increase protection against enteric pathogens.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 441-452"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023749","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":"Glial-immune interactions in barrier organs","authors":"Julia Karjalainen ,&nbsp;Sofia Hain ,&nbsp;Fränze Progatzky","doi":"10.1016/j.mucimm.2024.12.012","DOIUrl":"10.1016/j.mucimm.2024.12.012","url":null,"abstract":"<div><div>Neuro-immune interactions within barrier organs, such as lung, gut, and skin, are crucial in regulating tissue homeostasis, inflammatory responses, and host defence. Our rapidly advancing understanding of peripheral neuroimmunology is transforming the field of barrier tissue immunology, offering a fresh perspective for developing therapies for complex chronic inflammatory disorders affecting barrier organs. However, most studies have primarily examined interactions between the peripheral nervous system and the immune system from a neuron-focused perspective, while glial cells, the nonneuronal cells of the nervous system, have received less attention. Glial cells were long considered as mere bystanders, only supporting their neuronal neighbours, but recent discoveries mainly on enteric glial cells in the intestine have implicated these cells in immune-regulation and inflammatory disease pathogenesis. In this review, we will highlight the bi-directional interactions between peripheral glial cells and the immune system and discuss the emerging immune regulatory functions of glial cells in barrier organs.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 271-278"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882204","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":"Gut-homing and intestinal TIGITnegCD38+ memory T cells acquire an IL-12-induced, ex-Th17 pathogenic phenotype in a subgroup of Crohn’s disease patients with a severe disease course","authors":"Maud Heredia ,&nbsp;Daniëlle M.H. Barendregt ,&nbsp;Irma Tindemans ,&nbsp;Renz C.W. Klomberg ,&nbsp;Martine A. Aardoom ,&nbsp;Beatriz Calado ,&nbsp;Léa M.M. Costes ,&nbsp;Maria E. Joosse ,&nbsp;Daniëlle H. Hulleman-van Haaften ,&nbsp;Bastiaan Tuk ,&nbsp;Lisette A. van Berkel ,&nbsp;Polychronis Kemos ,&nbsp;Frank M. Ruemmele ,&nbsp;Nicholas M. Croft ,&nbsp;Johanna C. Escher ,&nbsp;Lissy de Ridder ,&nbsp;Janneke N. Samsom","doi":"10.1016/j.mucimm.2024.11.008","DOIUrl":"10.1016/j.mucimm.2024.11.008","url":null,"abstract":"<div><div>CD4⁺ memory T cell (T_M) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis. Defects driving loss of T_M regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38⁺T_M express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT⁺CD38⁺T_M have regulatory function while TIGIT^negCD38⁺T_M are enriched in IFN-γ-producing cells. We hypothesized TIGIT^negCD38⁺T_M are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGIT⁺CD38⁺T_M in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGIT^negCD38⁺T_M frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGIT^negCD38⁺T_M were highly enriched in HLA-DR⁺ and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated T_M identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGIT^negCD38⁺ phenotype. Moreover, <em>IL12RB2</em> mRNA expression was higher in TIGIT^negCD38⁺T_M than TIGIT⁺CD38⁺T_M, elevated in CD biopsies compared to controls, and correlated with severity of intestinal inflammation. Overall, we argue that in a subgroup of pediatric CD, increased IL-12 signaling drives reprogramming of Th17 to inflammatory Th1-like TIGIT^negCD38⁺T_M and causes more severe disease.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 299-311"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716443","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-33 is associated with alveolar dysfunction in patients with viral lower respiratory tract disease","authors":"Ian C. Scott ,&nbsp;Natalie van Zuydam ,&nbsp;Jennifer A. Cann ,&nbsp;Victor Augusti Negri ,&nbsp;Kalliopi Tsafou ,&nbsp;Helen Killick ,&nbsp;Zhi Liu ,&nbsp;Christopher McCrae ,&nbsp;D. Gareth Rees ,&nbsp;Elizabeth England ,&nbsp;Molly A. Guscott ,&nbsp;Kirsty Houslay ,&nbsp;Dominique McCormick ,&nbsp;Anna Freeman ,&nbsp;Darren Schofield ,&nbsp;Adrian Freeman ,&nbsp;E. Suzanne Cohen ,&nbsp;Ryan Thwaites ,&nbsp;Zach Brohawn ,&nbsp;Adam Platt ,&nbsp;Tom Wilkinson","doi":"10.1016/j.mucimm.2024.12.001","DOIUrl":"10.1016/j.mucimm.2024.12.001","url":null,"abstract":"<div><div>Interleukin (IL)-33 is released following tissue damage, causing airway inflammation and remodelling via reduced IL-33 (IL-33^red)/serum stimulation-2 (ST2) and oxidised IL-33 (IL-33^ox)/receptor for advanced glycation end products (RAGE)/epidermal growth factor receptor (EGFR) pathways. This study aimed to identify associations of IL-33 with clinical outcomes and pathological mechanisms during viral lower respiratory tract disease (LRTD). Ultra-sensitive immunoassays were developed to measure IL-33^red, IL-33^ox and IL-33/sST2 complexes in samples from patients hospitalised with COVID-19. Immunohistochemistry and multiomics were used to characterise lung samples. Elevated IL-33 in the airway and IL-33/sST2 complex in the circulation correlated with poor clinical outcomes (death, need for intensive care or mechanical ventilation). IL-33 was localised to airway epithelial and endothelial barriers, whereas <em>IL1RL1</em> was expressed on aerocytes, alveolar endothelial cells specialised for gaseous exchange. IL-33 increased expression of mediators of neutrophilic inflammation, immune cell infiltration, interferon signalling and coagulation in endothelial cell cultures. Endothelial IL-33 signatures were strongly related with signatures associated with viral LRTD. Increased IL-33 release following respiratory viral infections is associated with poor clinical outcomes and might contribute to alveolar dysfunction. Although this does not show a causal relationship with disease, these results provide a rationale to evaluate pathological roles for IL-33 in viral LRTD.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 312-325"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813824","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":"Mitochondrial damage-associated molecular patterns: New perspectives for mitochondria and inflammatory bowel diseases","authors":"Zhijie Wang ,&nbsp;Zixuan He ,&nbsp;Xin Chang ,&nbsp;Lu Xie ,&nbsp;Yihang Song ,&nbsp;Haicong Wu ,&nbsp;Hao Zhang ,&nbsp;Shuling Wang ,&nbsp;Xiaofeng Zhang ,&nbsp;Yu Bai","doi":"10.1016/j.mucimm.2025.01.013","DOIUrl":"10.1016/j.mucimm.2025.01.013","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 290-298"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","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}

{"title":"Targeting the EP2 receptor ameliorates inflammatory bowel disease in mice by enhancing the immunosuppressive activity of Treg cells","authors":"Chenchen Wang ,&nbsp;Tingting Yu ,&nbsp;Yuexin Wang ,&nbsp;Mengtong Xu ,&nbsp;Jingjing Wang ,&nbsp;Yan Zhao ,&nbsp;Qiangyou Wan ,&nbsp;Lu Wang ,&nbsp;Jie Yang ,&nbsp;Jie Zhou ,&nbsp;Bin Li ,&nbsp;Ying Yu ,&nbsp;Yujun Shen","doi":"10.1016/j.mucimm.2024.12.014","DOIUrl":"10.1016/j.mucimm.2024.12.014","url":null,"abstract":"<div><div>Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (T_reg) cells are crucial for maintaining self-tolerance and immune homeostasis in intestinal tissues. Prostaglandin E₂ (PGE₂), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE₂ regulates T_reg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE₂ receptor subtype 2 (EP2) is highly expressed in T_reg cells. T_reg cell-specific deletion of EP2 resulted in increased T_reg cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of T_reg cells in mice. Adoptive transfer of EP2-deficient T_reg cells attenuated naïve CD4⁺ T cell transfer-induced colitis in Rag1^−/− mice. Mice with EP2-deficient T_reg cells were protected from 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. Pharmacological blockage of EP2 with PF-04418948 markedly alleviated DSS-induced colitis in mice in a T_reg-dependent manner. Mechanistically, activation of EP2 suppressed T_reg cell function, at least in part, through reduction of GzmB expression via PKA-mediated inhibition of NF-κB signaling. Thus, we identified the PGE₂/EP2 axis as a key negative modulator of T_reg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 418-430"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922095","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":"Tissue-resident natural killer cells derived from conventional natural killer cells are regulated by progesterone in the uterus","authors":"Bruna K. Tatematsu,&nbsp;Dorothy K. Sojka","doi":"10.1016/j.mucimm.2024.12.009","DOIUrl":"10.1016/j.mucimm.2024.12.009","url":null,"abstract":"<div><div>The murine uterus contains three subsets of innate lymphoid cells (ILCs). Innate lymphoid cell type 1 (ILC1) and conventional natural killer (cNK) cells seed the uterus before puberty. Tissue-resident NK (trNK) cells emerge at puberty and vary in number during the estrous cycle. Here, we addressed the origin of uterine trNK cells and the influence of ovarian hormones on their local activation and differentiation <em>in vivo.</em> We used parabiosed mice in combination with intravascular fluorescent antibody labeling and flow cytometry to distinguish tissue-resident from circulating immune cells. Additionally, we used C57BL/6J ovariectomized (OVX) and non-OVX mice supplemented with ovarian hormones to assess their effects on uterine trNK cell function. Strikingly, mice OVX at three weeks of age and analyzed as adults lacked uterine trNK cells unless progesterone was administered. Our parabiosis studies confirmed that the progesterone-responsive trNK cells are derived from peripheral cNK cells. Moreover, medroxyprogesterone 17-acetate-induced expansion of cNK-derived trNK cells was abolished by a progesterone receptor antagonist. These data reveal a novel, uterine-specific differentiation pathway of trNK cells that is tightly regulated by progesterone.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 390-401"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872606","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":"TIFA renders intestinal epithelial cells responsive to microbial ADP-heptose and drives colonic inflammation in mice","authors":"Lena Erkert ,&nbsp;Barbara Ruder ,&nbsp;Melanie Kabisch ,&nbsp;Reyes Gamez Belmonte ,&nbsp;Jay V. Patankar ,&nbsp;Miguel Gonzalez Acera ,&nbsp;Lena Schödel ,&nbsp;Mircea T. Chiriac ,&nbsp;Roodline Cineus ,&nbsp;Stylianos Gnafakis ,&nbsp;Tamara Leupold ,&nbsp;Oana-Maria Thoma ,&nbsp;Iris Stolzer ,&nbsp;Astrid Taut ,&nbsp;Veronika Thonn ,&nbsp;Sebastian Zundler ,&nbsp;Claudia Günther ,&nbsp;Andreas Diefenbach ,&nbsp;Anja A. Kühl ,&nbsp;Ahmed N. Hegazy ,&nbsp;Sebastian Zundler","doi":"10.1016/j.mucimm.2025.01.003","DOIUrl":"10.1016/j.mucimm.2025.01.003","url":null,"abstract":"<div><div>Intestinal immune homeostasis relies on intestinal epithelial cells (IECs), which provide an efficient barrier, and warrant a state of tolerance between the microbiome and the mucosal immune system. Thus, proper epithelial microbial sensing and handling of microbes is key to preventing excessive immunity, such as seen in patients with inflammatory bowel disease (IBD). To date, the molecular underpinnings of these processes remain incompletely understood. This study identifies TIFA as a driver of intestinal inflammation and an epithelial signaling hub between the microbiome and mucosal immune cells. TIFA was constitutively expressed in crypt epithelial cells and was highly induced in the intestine of mice and IBD patients with intestinal inflammation. We further identified IL-22 signaling via STAT3 as key mechanism driving TIFA expression in IECs. At the molecular level, we demonstrate that TIFA expression is essential for IEC responsiveness to the bacterial metabolite ADP-heptose. Most importantly, ADP-heptose-induced TIFA signaling orchestrates an inflammatory cellular response in the epithelium, with NF-κB and inflammasome activation, and high levels of chemokine production. Finally, mice lacking TIFA were protected from intestinal inflammation when subjected to a model of experimental colitis. In conclusion, our study implicates that targeting TIFA may be a strategy for future IBD therapy.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 2","pages":"Pages 453-466"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023987","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}