Mucosal ImmunologyPub Date : 2025-08-18DOI: 10.1016/j.mucimm.2025.08.002
Lauren E Springer, Han-Zhi Rao, Oliver Abinader, Ramkrishna Mitra, Christopher M Snyder
{"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":"https://doi.org/10.1016/j.mucimm.2025.08.002","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-08-18","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}
Mucosal ImmunologyPub Date : 2025-08-16DOI: 10.1016/j.mucimm.2025.08.004
Jeffrey R Maslanka, Jennifer A Londregan, Joshua E Denny, Ellie N Hulit, Nontokozo V Mdluli, F Christopher Peritore-Galve, Md Zahidul Alam, Mohamad-Gabriel Alameh, D Borden Lacy, Joseph P Zackular, Michael C Abt
{"title":"Clostridioides difficile toxin A and toxin B inhibit toxin-specific adaptive immune responses through glucosyltransferase-dependent activity.","authors":"Jeffrey R Maslanka, Jennifer A Londregan, Joshua E Denny, Ellie N Hulit, Nontokozo V Mdluli, F Christopher Peritore-Galve, Md Zahidul Alam, Mohamad-Gabriel Alameh, D Borden Lacy, Joseph P Zackular, Michael C Abt","doi":"10.1016/j.mucimm.2025.08.004","DOIUrl":"10.1016/j.mucimm.2025.08.004","url":null,"abstract":"<p><p>Clostridioides difficile colonizes the gastrointestinal tract and secretes two virulence factors: toxin A (TcdA) and toxin B (TcdB). Protective immunity against C. difficile infection is limited as patients are susceptible to multiple rounds of recurrent infections. The factors determining whether immunity to TcdA and TcdB is generated remain incompletely defined. We determined that C. difficile-infected mice generate antibody and IL-17A-producing CD4<sup>+</sup> T cell responses to TcdA but not TcdB. To determine the mechanism of the failed anti-TcdB immunity, C. difficile mutant strains expressing glucosyltransferase inactive (GTX) TcdA, and/or glucosyltransferase inactive TcdB were used. Infection with TcdB<sub>GTX</sub> or dual mutant (TcdA<sub>GTX</sub> TcdB<sub>GTX</sub>) restored TcdB-specific antibody responses, while infection with TcdA<sub>GTX</sub> or TcdA<sub>GTX</sub> TcdB<sub>GTX</sub> led to an earlier induction of TcdA-specific antibodies. Finally, infection with the dual GTX mutant enhanced TcdA and TcdB-specific CD4<sup>+</sup> T cell responses. These data demonstrate that the glucosyltransferase activity of TcdA and TcdB hinders the antigen-specific adaptive immune response to itself and may be a mechanism that underlies high recurrence rates following C. difficile infection in patients.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874208","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 ImmunologyPub Date : 2025-08-15DOI: 10.1016/j.mucimm.2025.08.005
Kunal Dhume, Caroline M Finn, Eugene Baffoe, Lauren A Kimball, Siva N Annamalai, Verónica Urdaneta-Páez, Jash Trivedi, Taj Azarian, Tara M Strutt, K Kai McKinstry
{"title":"T-cell immunity against influenza virus does not require Th1 or Th17 master regulator transcription factors.","authors":"Kunal Dhume, Caroline M Finn, Eugene Baffoe, Lauren A Kimball, Siva N Annamalai, Verónica Urdaneta-Páez, Jash Trivedi, Taj Azarian, Tara M Strutt, K Kai McKinstry","doi":"10.1016/j.mucimm.2025.08.005","DOIUrl":"10.1016/j.mucimm.2025.08.005","url":null,"abstract":"<p><p>Transcriptional programming needed for CD4 T cell immunity against influenza A virus (IAV) is unclear. Most antiviral CD4 T cells fit Th1 criteria, but cells unable to develop Th1 identity, through deletion of the transcription factors T-bet and Eomesodermin, remain protective. These double knockout (DKO) cells produce Th17 cytokines and express the Th17 'master regulator', Rorγt, supporting the concept that Th17 programming is needed for Th1-independent T cell immunity. Here, we directly tested requirements for Rorγt in promoting this mode of protection using T-bet/Eomesodermin/Rorγt triple knockout (TKO) mice. We show that Th17 functions are dramatically reduced in TKO cells but that they can nevertheless transfer protection against IAV to unprimed wildtype mice. Furthermore, TKO mice efficiently clear primary IAV infection, resist lethal bacterial superinfection, and generate antibody-dependent immunity against reinfection with the same virus. Finally, T cell-dependent heterosubtypic immunity is similarly effective in IAV-primed TKO, DKO, and wildtype mice. However, strikingly different T cell response patterns and inflammatory landscapes underlie these protective outcomes, highlighted in TKO mice by Th2-linked components not typically associated with efficient viral clearance. Our results reveal an unexpected degree of flexibility in T cell responses able to combat IAV, underscoring their potential to enhance vaccine strategies.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874209","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 ImmunologyPub Date : 2025-08-13DOI: 10.1016/j.mucimm.2025.08.001
Gerald J O'Connor, Rachel M Wigmore, Nguyen T Van, Jihae C Choi, Karen Zhang, Charles Kivolowitz, Alessandra Chen, Manju Ambelil, Dan R Littman, Sangwon V Kim
{"title":"C10ORF99 (GPR15L) increases susceptibility to colitis and colitis-induced colorectal cancer via GPR15-independent mechanisms, while mediating GPR15-dependent T cell migration to the large intestine.","authors":"Gerald J O'Connor, Rachel M Wigmore, Nguyen T Van, Jihae C Choi, Karen Zhang, Charles Kivolowitz, Alessandra Chen, Manju Ambelil, Dan R Littman, Sangwon V Kim","doi":"10.1016/j.mucimm.2025.08.001","DOIUrl":"10.1016/j.mucimm.2025.08.001","url":null,"abstract":"<p><p>GPR15 is a homing receptor important for T cell migration to the large intestine, the primary site of inflammation in ulcerative colitis. Both GPR15 and its ligand, C10ORF99, represent potential therapeutic targets for the treatment of IBD; however, the roles of C10ORF99 in the large intestine are not fully elucidated. Here, we demonstrate that C10ORF99 is the non-redundant ligand of GPR15 mediating T cell migration to the large intestine. Furthermore, we demonstrate that C10ORF99 has GPR15-independent functions in the large intestine: C10ORF99 deficiency is protective in chemically induced colitis, and this appears to result from enhanced epithelial barrier regeneration. We found that C10ORF99 can inhibit intestinal epithelial proliferation in a cell-intrinsic manner. Additionally, due to this protection from colitis development in the absence of C10ORF99, C10ORF99 KO is also protected from colitis-associated colorectal cancer development. These data indicate that the deficiency of C10ORF99 can not only block pathogenic T cell migration to the large intestine, but can also promote epithelial barrier repair, potentially offering additional advantages for recovery from ulcerative colitis.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859369","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 ImmunologyPub Date : 2025-08-13DOI: 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, Alexander García-Ponce, Jens Waschke, Sven Flemming, Kai Kretzschmar, Nicolas Schlegel
{"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, Alexander García-Ponce, Jens Waschke, Sven Flemming, Kai Kretzschmar, Nicolas Schlegel","doi":"10.1016/j.mucimm.2025.08.003","DOIUrl":"10.1016/j.mucimm.2025.08.003","url":null,"abstract":"<p><p>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 (iVilCreER<sup>T2</sup>Jup<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 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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-08-13","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}
Mucosal ImmunologyPub Date : 2025-08-01DOI: 10.1016/j.mucimm.2025.04.004
Rodrigo A. Morales Castro , Bianca C. Kern , Angélica Díaz-Basabe , Eveline R. Meinen , Danxia Zhao , Yuqing Zhou , Francisca Castillo , Gustavo Monasterio , Vlad Farcas , Myra N. Chávez , Jennifer Fransson , Eduardo J. Villablanca
{"title":"A zebrafish model of intestinal epithelial damage reveals macrophages and igfbp1a as major modulators of mucosal healing","authors":"Rodrigo A. Morales Castro , Bianca C. Kern , Angélica Díaz-Basabe , Eveline R. Meinen , Danxia Zhao , Yuqing Zhou , Francisca Castillo , Gustavo Monasterio , Vlad Farcas , Myra N. Chávez , Jennifer Fransson , Eduardo J. Villablanca","doi":"10.1016/j.mucimm.2025.04.004","DOIUrl":"10.1016/j.mucimm.2025.04.004","url":null,"abstract":"<div><div>Promoting intestinal regeneration and enhancing mucosal healing have emerged as promising therapeutic alternatives for treating intestinal disorders that compromise epithelial barrier integrity and function. However, the cellular and molecular mechanisms underlying these processes remain poorly understood. This knowledge gap is partly due to the lack of reliable and cost-effective <em>in vivo</em> models for studying the mechanisms governing intestinal damage and regeneration. Here, we developed a controlled, inducible, and targeted intestinal epithelial cell (IEC) ablation transgenic zebrafish model that recapitulates features of intestinal damage and regeneration observed in humans. Single-cell RNAseq and live imaging revealed accumulation of macrophages in the recovering intestine, contributing to its regeneration. Furthermore, we observed overexpression of insulin-like growth factor binding protein 1a (<em>igfbp1a</em>) during intestinal damage. Morpholino-mediated knockdown of <em>igfbp1a</em> exacerbated intestinal damage and impaired subsequent regeneration. In summary, we introduced a novel zebrafish model of intestinal damage that enables <em>in vivo</em> high-throughput screening for identifying and validating novel modulators of mucosal healing and intestinal regeneration.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 836-847"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025134","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 ImmunologyPub Date : 2025-08-01DOI: 10.1016/j.mucimm.2025.05.006
Liyen Loh , David J. Orlicky , Andrea Spengler , Joanne Domenico , Jared Klarquist , Cassandra Levens , Sofia Celli , Jennifer M. Kofonow , Charles E. Robertson , Olivier Lantz , Francois Legoux , Daniel N. Frank , Jennifer Matsuda , Paul J. Norman , Kristine A. Kuhn , Joseph Onyiah , Laurent Gapin
{"title":"MAIT cells exacerbate colonic inflammation in a genetically diverse murine model of spontaneous colitis","authors":"Liyen Loh , David J. Orlicky , Andrea Spengler , Joanne Domenico , Jared Klarquist , Cassandra Levens , Sofia Celli , Jennifer M. Kofonow , Charles E. Robertson , Olivier Lantz , Francois Legoux , Daniel N. Frank , Jennifer Matsuda , Paul J. Norman , Kristine A. Kuhn , Joseph Onyiah , Laurent Gapin","doi":"10.1016/j.mucimm.2025.05.006","DOIUrl":"10.1016/j.mucimm.2025.05.006","url":null,"abstract":"<div><div>IL-17-producing lymphocytes are involved in both tissue repair and the propagation of inflammation, with their effects highly context-dependent. Mucosal-Associated-Invariant-T-cells (MAIT), a subset of innate-like T cells with features of both Th1 and Th17 lineages, are increasingly recognized for their roles in mucosal immunity. Here, we identified the Collaborative-Cross CC011/Unc strain, which spontaneously develops chronic colitis, as being enriched for MAIT cells. This expansion coincides with an age-related loss of intestinal barrier permeability and colonic inflammation. Microbiota from CC011 mice activated MAIT cells in an MR1-dependent manner and selectively promoted the accumulation of MAIT17 cells in peripheral tissues. Single-cell transcriptomic analyses revealed colon MAIT cells from colitic CC011 mice expressed a pathogenic Th17-like signature, characterized by IL-1 and IL-23 signaling, IL-17A and IFNγ co-expression, and upregulation of IL-23R, features that correlated with inflammatory Ly6C<sup>hi</sup> monocyte abundance. Genetic deletion of <em>Traj33</em>, essential for MAIT development, significantly reduced colonic inflammation in this model. These findings demonstrate that MAIT cells integrate microbial and cytokine cues to adopt a pathogenic effector phenotype that exacerbates chronic intestinal inflammation.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 958-972"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160548","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 ImmunologyPub Date : 2025-08-01DOI: 10.1016/j.mucimm.2025.04.007
Alexander D. Ethridge , Kazuma Yagi , Llilian Arzola Martínez , Andrew J. Rasky , Susan B. Morris , Nicole R. Falkowski , Gary B. Huffnagle , Nicholas W. Lukacs
{"title":"RSV infection in neonatal mice and gastrointestinal microbiome alteration contribute to allergic predisposition","authors":"Alexander D. Ethridge , Kazuma Yagi , Llilian Arzola Martínez , Andrew J. Rasky , Susan B. Morris , Nicole R. Falkowski , Gary B. Huffnagle , Nicholas W. Lukacs","doi":"10.1016/j.mucimm.2025.04.007","DOIUrl":"10.1016/j.mucimm.2025.04.007","url":null,"abstract":"<div><div>Severe respiratory syncytial virus (RSV) infection during infancy is associated with a 2 to 4-fold increased risk for the development of wheezing and asthma. Recent studies have implicated microbiome changes, either within the lung or gut, during early life can also affect the development of pulmonary disease. Our studies demonstrate long-term gastrointestinal and lung microbiome changes following early life (EL) RSV infection. To determine the respective roles of ELRSV infection and the gut microbiome, we performed germ-free neonatal infection and microbiome colonization using a microbiome from an uninfected animal followed by cockroach allergen (CRA)-induced asthma 4 weeks later. Germ-free animals with ELRSV infection displayed increased airway disease that was diminished by microbiome colonization, including airway hyperreactivity (AHR), mucus, and eosinophil infiltration. To address the role of virus induced gastrointestinal microbiome alterations, we utilized GF mice conventionalized with RSV-associated or naive microbiomes followed by CRA-induced disease. Transfer of neonatal microbiome taken during acute RSV infection did not alter the allergic response to CRA. However, the transfer of a naive adult microbiome conferred protection from enhanced AHR in response to CRA whereas an RSV associated microbiome did not. Taken together, our data indicate that microbiome alteration and early life RSV infection both contribute to allergic predisposition.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 874-886"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993945","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 ImmunologyPub Date : 2025-08-01DOI: 10.1016/j.mucimm.2025.05.003
Yixuan D. Zhou , Macy R. Komnick , Fabiola Sepulveda , Grace Liu , Elida Nieves-Ortiz , Kelsey Meador , Ornella Ndatabaye , Aliia Fatkhullina , Asha Bozicevich , Braden Juengel , Natalie J. Wu-Woods , Paulina M. Naydenkov , Johnathan Kent , Nathaniel Christiansen , Maria Lucia Madariaga , Piotr Witkowski , Rustem F. Ismagilov , Daria Esterházy
{"title":"Inducible, but not constitutive, pancreatic REG/Reg isoforms are regulated by intestinal microbiota and pancreatic diseases","authors":"Yixuan D. Zhou , Macy R. Komnick , Fabiola Sepulveda , Grace Liu , Elida Nieves-Ortiz , Kelsey Meador , Ornella Ndatabaye , Aliia Fatkhullina , Asha Bozicevich , Braden Juengel , Natalie J. Wu-Woods , Paulina M. Naydenkov , Johnathan Kent , Nathaniel Christiansen , Maria Lucia Madariaga , Piotr Witkowski , Rustem F. Ismagilov , Daria Esterházy","doi":"10.1016/j.mucimm.2025.05.003","DOIUrl":"10.1016/j.mucimm.2025.05.003","url":null,"abstract":"<div><div>The <em>REG</em>/<em>Reg</em> gene locus encodes a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether <em>REG/Reg</em> family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in humans and mice, the pancreas and gut differed in <em>REG</em>/<em>Reg</em> isoform levels and preferences, with the duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select <em>Reg</em> members in gut and pancreas. These <em>Reg</em> members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as “inducible” and others as “constitutive”. Indeed, in pancreatic ductal adenocarcinoma and pancreatitis models, only inducible <em>Reg</em> members were upregulated in the pancreas. While intestinal <em>Reg</em> expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of <em>REG</em>/<em>Reg</em> isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated <em>Reg</em> response.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 918-936"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120342","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
