Pub Date : 2025-12-21DOI: 10.1016/j.mucimm.2025.12.001
Yang Gu, Chuan Wu
The intestine and liver are physically interconnected through the biliary system, portal circulation, lymphatic network, and neural pathways, collectively forming the gut-liver axis. The gut-liver axis and the immune system are engaged in a complex regulatory relationship. Over the past few decades, significant progress has been made in elucidating how liver-derived bile acids (BAs) shape intestinal immunity through interactions with the gut microbiota. However, the multidirectional regulatory pathways by which the liver orchestrates intestinal immune homeostasis remain incompletely defined. In this review, we highlight liver-derived cues-including the BAs, neural signals, nutrient metabolism, hormones, hepatically secreted proteins, and the complement system-and their impact on intestinal innate and adaptive immune cells. Furthermore, we discuss how intestinal dysbiosis contributes to the progression of liver inflammation and hepatocellular carcinoma (HCC) via immune cells. A comprehensive understanding of these intricate interactions may uncover novel therapeutic strategies for treating gut- and liver-associated immune disorders.
{"title":"The gut-liver axis modulates intestinal immune homeostasis.","authors":"Yang Gu, Chuan Wu","doi":"10.1016/j.mucimm.2025.12.001","DOIUrl":"10.1016/j.mucimm.2025.12.001","url":null,"abstract":"<p><p>The intestine and liver are physically interconnected through the biliary system, portal circulation, lymphatic network, and neural pathways, collectively forming the gut-liver axis. The gut-liver axis and the immune system are engaged in a complex regulatory relationship. Over the past few decades, significant progress has been made in elucidating how liver-derived bile acids (BAs) shape intestinal immunity through interactions with the gut microbiota. However, the multidirectional regulatory pathways by which the liver orchestrates intestinal immune homeostasis remain incompletely defined. In this review, we highlight liver-derived cues-including the BAs, neural signals, nutrient metabolism, hormones, hepatically secreted proteins, and the complement system-and their impact on intestinal innate and adaptive immune cells. Furthermore, we discuss how intestinal dysbiosis contributes to the progression of liver inflammation and hepatocellular carcinoma (HCC) via immune cells. A comprehensive understanding of these intricate interactions may uncover novel therapeutic strategies for treating gut- and liver-associated immune disorders.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820006","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 : 2025-12-21DOI: 10.1016/j.mucimm.2025.12.002
Heyde Makimaa, Harshad Ingle, Leran Wang, Somya Aggarwal, Hongju Deng, Elizabeth A Kennedy, Lynne Foster, Yuhao Li, Megan T Baldridge
Human astroviruses (HAstVs) are a global cause of pediatric gastroenteritis and can cause disseminated infection in immunocompromised hosts. Murine astrovirus (muAstV) causes acute asymptomatic infections in immunocompetent mice and chronic infection in immunodeficient models and has provided important insights into AstV pathogenesis in vivo. MuAstV can protect immunodeficient mice from other enteric viruses via robust induction of antiviral cytokine interferon-lambda (IFN-λ), with recent findings implicating goblet cells and enterocytes as both cell types infected by muAstV as well as potential sources of IFN-λ in vivo. However, the viral sensing pathways that regulate induction of IFN-λ, as well as the specific activity of IFN-λ in viral control and regulation of cellular tropism, remain to be defined for muAstV. Here, we leveraged single-cell RNA sequencing (scRNA-seq) to provide additional evidence of muAstV tropism for multiple intestinal epithelial cells (IECs) including goblet cells and diverse enterocyte types. Significantly, enterocytes appear to serve as the dominant source of IFN-λ in response to muAstV infection. Moreover, we report that this induction of IFN-λ in response to muAstV is regulated by the MDA5-MAVS pathway, with enhanced infection and expansion of infected cell numbers observed when either Mda5 or Mavs is disrupted. Leveraging mice conditionally deficient for Ifnlr1 or Mavs, we characterized the specific cellular requirements for IFN-λ signaling and MAVS to control muAstV infection. While IFN-λ signaling acts predominantly on secretory cells, including goblet cells, to limit muAstV infection, we found that IECs broadly require MAVS to control muAstV but with no specific IEC type implicated, suggesting a potential synergistic requirement across IECs. Our study highlights the MDA5-MAVS-IFN-λ signaling axis as critical for regulation of muAstV infection, providing further insights into the innate immune regulation of this enteric pathogen.
{"title":"MDA5-MAVS and interferon-lambda signaling in the intestinal epithelium limit murine astrovirus infection.","authors":"Heyde Makimaa, Harshad Ingle, Leran Wang, Somya Aggarwal, Hongju Deng, Elizabeth A Kennedy, Lynne Foster, Yuhao Li, Megan T Baldridge","doi":"10.1016/j.mucimm.2025.12.002","DOIUrl":"10.1016/j.mucimm.2025.12.002","url":null,"abstract":"<p><p>Human astroviruses (HAstVs) are a global cause of pediatric gastroenteritis and can cause disseminated infection in immunocompromised hosts. Murine astrovirus (muAstV) causes acute asymptomatic infections in immunocompetent mice and chronic infection in immunodeficient models and has provided important insights into AstV pathogenesis in vivo. MuAstV can protect immunodeficient mice from other enteric viruses via robust induction of antiviral cytokine interferon-lambda (IFN-λ), with recent findings implicating goblet cells and enterocytes as both cell types infected by muAstV as well as potential sources of IFN-λ in vivo. However, the viral sensing pathways that regulate induction of IFN-λ, as well as the specific activity of IFN-λ in viral control and regulation of cellular tropism, remain to be defined for muAstV. Here, we leveraged single-cell RNA sequencing (scRNA-seq) to provide additional evidence of muAstV tropism for multiple intestinal epithelial cells (IECs) including goblet cells and diverse enterocyte types. Significantly, enterocytes appear to serve as the dominant source of IFN-λ in response to muAstV infection. Moreover, we report that this induction of IFN-λ in response to muAstV is regulated by the MDA5-MAVS pathway, with enhanced infection and expansion of infected cell numbers observed when either Mda5 or Mavs is disrupted. Leveraging mice conditionally deficient for Ifnlr1 or Mavs, we characterized the specific cellular requirements for IFN-λ signaling and MAVS to control muAstV infection. While IFN-λ signaling acts predominantly on secretory cells, including goblet cells, to limit muAstV infection, we found that IECs broadly require MAVS to control muAstV but with no specific IEC type implicated, suggesting a potential synergistic requirement across IECs. Our study highlights the MDA5-MAVS-IFN-λ signaling axis as critical for regulation of muAstV infection, providing further insights into the innate immune regulation of this enteric pathogen.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820002","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.2025.10.001
Hiba Hasan , Christiane Pleuger , Dingding Ai , Sudhanshu Bhushan , Eva Wahle , Tara Procida-Kowalski , Qunxiong Zeng , Rukmali Wijayarathna , Claire Xin Sun , Yong-Gang Duan , Daniela Fietz , Marek Bartkuhn , Hans-Christian Schuppe , Adrian Pilatz , Kate L. Loveland , Andreas Meinhardt , Mark P. Hedger , Monika Fijak
Uropathogenic Escherichia coli is a common pathogen that affects the cauda epididymidis, causing interstitial edema, epithelial damage, leukocyte infiltration, and fibrosis. Despite antibiotic treatment, up to 20 % of patients develop abscesses in the cauda epididymidis, and 40 % experience low sperm counts. To understand the mechanisms of infertility impairment caused by epididymitis, we aimed to investigate the histopathological and immunological changes affecting the cauda epididymidis focusing on later post-acute stages of UPEC infection. Using a bacterial mouse model of acute epididymitis, we identified organized tertiary lymphoid organs (TLOs) that formed in the cauda epididymidis at 28 days post-infection. These appear as compartmentalized B- and T-cell clusters containing high endothelial venules (HEV) with evidence of an active germinal centre. Transcriptomic analysis confirmed the existence of a supportive microenvironment conducive to TLO formation and maintenance. Furthermore, TLO formation was also observed in human cauda epididymidis following chronic epididymitis, as documented by the presence of B- and T-cell clusters adjacent to HEV. Elevated concentrations of CXCL13 were measured in sera from epididymitis patients in acute and post-acute phase of disease. Our data suggest that TLOs in the cauda epididymidis harbor a functionally active germinal centre, which may impact male fertility in the long term.
{"title":"Epididymitis promotes formation of tertiary lymphoid organs in the cauda epididymidis","authors":"Hiba Hasan , Christiane Pleuger , Dingding Ai , Sudhanshu Bhushan , Eva Wahle , Tara Procida-Kowalski , Qunxiong Zeng , Rukmali Wijayarathna , Claire Xin Sun , Yong-Gang Duan , Daniela Fietz , Marek Bartkuhn , Hans-Christian Schuppe , Adrian Pilatz , Kate L. Loveland , Andreas Meinhardt , Mark P. Hedger , Monika Fijak","doi":"10.1016/j.mucimm.2025.10.001","DOIUrl":"10.1016/j.mucimm.2025.10.001","url":null,"abstract":"<div><div>Uropathogenic <em>Escherichia coli</em> is a common pathogen that affects the cauda epididymidis, causing interstitial edema, epithelial damage, leukocyte infiltration, and fibrosis. Despite antibiotic treatment, up to 20 % of patients develop abscesses in the cauda epididymidis, and 40 % experience low sperm counts. To understand the mechanisms of infertility impairment caused by epididymitis, we aimed to investigate the histopathological and immunological changes affecting the cauda epididymidis focusing on later post-acute stages of UPEC infection. Using a bacterial mouse model of acute epididymitis, we identified organized tertiary lymphoid organs (TLOs) that formed in the cauda epididymidis at 28 days post-infection. These appear as compartmentalized B- and T-cell clusters containing high endothelial venules (HEV) with evidence of an active germinal centre. Transcriptomic analysis confirmed the existence of a supportive microenvironment conducive to TLO formation and maintenance. Furthermore, TLO formation was also observed in human cauda epididymidis following chronic epididymitis, as documented by the presence of B- and T-cell clusters adjacent to HEV. Elevated concentrations of CXCL13 were measured in sera from epididymitis patients in acute and post-acute phase of disease. Our data suggest that TLOs in the cauda epididymidis harbor a functionally active germinal centre, which may impact male fertility in the long term.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1405-1423"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275228","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.2025.09.003
Anika Fuhr , Meike Goerlich , Anna Biedritzky , Carolin Kleinmaier , Ka-Lin Heck-Swain , Jutta Gamper-Tsigaras , Kristian-Christos Ngamsri , Franziska Konrad , Michael Koeppen
Acute respiratory distress syndrome (ARDS) is characterized by excessive neutrophil recruitment, endothelial barrier dysfunction, and persistent inflammation. A Disintegrin and Metalloproteinase 10 (ADAM10) regulates leukocyte trafficking by cleaving adhesion molecules such as VE-cadherin and JAM-A, but its role in neutrophil-driven lung injury remains unclear. We investigated whether neutrophil-derived ADAM10 modulates neutrophil adhesion, migration, and pulmonary inflammation in a murine model of ARDS and assessed the effects of systemic ADAM10 inhibition.
Using a neutrophil-specific ADAM10 knockout mouse model (ADAM10loxP/loxPCatchup-Cre+) and pharmacological ADAM10 inhibition, we evaluated neutrophil recruitment, endothelial permeability, and adhesion molecule expression in lipopolysaccharide (LPS)-induced lung inflammation. Flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to assess neutrophil migration, activation, and cytokine release. In vitro adhesion and transmigration assays were performed with human endothelial and epithelial monolayers using freshly isolated human neutrophils.
Neutrophil-specific ADAM10 deletion did not affect endothelial permeability but reduced neutrophil recruitment into the alveolar space, associated with decreased CXCL1 and CXCL2/3 secretion and increased CD44 surface expression. ADAM10 inhibition enhanced adhesion but impaired transmigration, mirroring genetic deletion. Systemic inhibition also suppressed neutrophil activation and inflammatory cytokine release.
Neutrophil ADAM10 promotes neutrophil migration and inflammation in ARDS by modulating chemokine signaling and adhesion molecule expression. Systemic ADAM10 inhibition reduces neutrophil infiltration and inflammatory cytokine production, suggesting ADAM10 as a potential therapeutic target to mitigate neutrophil-driven lung injury.
{"title":"Neutrophil ADAM10 promotes migration and inflammation in ARDS by modulating adhesion and chemokine signaling","authors":"Anika Fuhr , Meike Goerlich , Anna Biedritzky , Carolin Kleinmaier , Ka-Lin Heck-Swain , Jutta Gamper-Tsigaras , Kristian-Christos Ngamsri , Franziska Konrad , Michael Koeppen","doi":"10.1016/j.mucimm.2025.09.003","DOIUrl":"10.1016/j.mucimm.2025.09.003","url":null,"abstract":"<div><div>Acute respiratory distress syndrome (ARDS) is characterized by excessive neutrophil recruitment, endothelial barrier dysfunction, and persistent inflammation. <em>A Disintegrin and Metalloproteinase 10</em> (ADAM10) regulates leukocyte trafficking by cleaving adhesion molecules such as VE-cadherin and JAM-A, but its role in neutrophil-driven lung injury remains unclear. We investigated whether neutrophil-derived ADAM10 modulates neutrophil adhesion, migration, and pulmonary inflammation in a murine model of ARDS and assessed the effects of systemic ADAM10 inhibition.</div><div>Using a neutrophil-specific ADAM10 knockout mouse model (<em>ADAM10<sup>loxP/loxP</sup></em>Catchup-Cre+) and pharmacological ADAM10 inhibition, we evaluated neutrophil recruitment, endothelial permeability, and adhesion molecule expression in lipopolysaccharide (LPS)-induced lung inflammation. Flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to assess neutrophil migration, activation, and cytokine release. In vitro adhesion and transmigration assays were performed with human endothelial and epithelial monolayers using freshly isolated human neutrophils.</div><div>Neutrophil-specific ADAM10 deletion did not affect endothelial permeability but reduced neutrophil recruitment into the alveolar space, associated with decreased CXCL1 and CXCL2/3 secretion and increased CD44 surface expression. ADAM10 inhibition enhanced adhesion but impaired transmigration, mirroring genetic deletion. Systemic inhibition also suppressed neutrophil activation and inflammatory cytokine release.</div><div>Neutrophil ADAM10 promotes neutrophil migration and inflammation in ARDS by modulating chemokine signaling and adhesion molecule expression. Systemic ADAM10 inhibition reduces neutrophil infiltration and inflammatory cytokine production, suggesting ADAM10 as a potential therapeutic target to mitigate neutrophil-driven lung injury<em>.</em></div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1353-1365"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065350","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.2025.11.002
Ann M. Joseph , Anees Ahmed , Jeremy Goc , Veronika Horn , Brooke Fiedler , Dario Garone , John B. Grigg , Jazib Uddin , Fei Teng , Melanie Fritsch , Eric Vivier , Gregory F. Sonnenberg
{"title":"Corrigendum “RIPK3 and Caspase-8 interpret cytokine signals to regulate ILC3 survival in the gut”. [Mucosal Immunol. 17/6 (2024) 1212–1221]","authors":"Ann M. Joseph , Anees Ahmed , Jeremy Goc , Veronika Horn , Brooke Fiedler , Dario Garone , John B. Grigg , Jazib Uddin , Fei Teng , Melanie Fritsch , Eric Vivier , Gregory F. Sonnenberg","doi":"10.1016/j.mucimm.2025.11.002","DOIUrl":"10.1016/j.mucimm.2025.11.002","url":null,"abstract":"","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1464-1465"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530802","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.2025.08.005
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
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.
{"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":"<div><div>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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1284-1297"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","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}
Pub Date : 2025-12-01DOI: 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
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+ 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 TcdBGTX or dual mutant (TcdAGTX TcdBGTX) restored TcdB-specific antibody responses, while infection with TcdAGTX or TcdAGTX TcdBGTX led to an earlier induction of TcdA-specific antibodies. Finally, infection with the dual GTX mutant enhanced TcdA and TcdB-specific CD4+ 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.
{"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":"<div><div><em>Clostridioides difficile</em> colonizes the gastrointestinal tract and secretes two virulence factors: toxin A (TcdA) and toxin B (TcdB). Protective immunity against <em>C. difficile</em> 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 <em>C. difficile</em>-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, <em>C. difficile</em> 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 <em>C. difficile</em> infection in patients.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1271-1283"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","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}
Pub Date : 2025-12-01DOI: 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
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.
{"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":"<div><div>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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1229-1239"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","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}
Pub Date : 2025-12-01DOI: 10.1016/j.mucimm.2025.10.003
Sarah Berger , Cengiz Goekeri , Peter Pennitz , Birgitt Gutbier , Laura Michalick , Karen Hoffmann , Elena Lopez-Rodriguez , Vladimir Gluhovic , Sandra-Maria Wienhold , Ulrike Behrendt , Alexander Taylor , Kristina Dietert , Holger Kirsten , Sandra Kunder , Kristina Mueller , Markus Weigel , Torsten Hain , Sarah M. Volkers , Sebastian Weis , Achim D. Gruber , Geraldine Nouailles
Acute lung injury is a common complication of pneumonia, with disease severity linked to inflammatory cell recruitment and lung barrier dysfunction. In this study, we investigate the role of neutrophil-chemoattractant CXCL5 in lung barrier function and inflammation.
We examined CXCL5 in patients with severe pneumonia and in in vitro and in vivo models of acute lung injury. Pneumococcal infection and mechanical ventilation triggered CXCL5 release in both humans and mice. In Cxcl5-deficient mice, the alveolar-epithelial barrier remained intact despite acute lung injury, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial cells of Cxcl5-deficient mice. Consistently, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells.
Beyond its known role in neutrophil recruitment, CXCL5 independently increases alveolar-epithelial barrier permeability. Therefore, targeting CXCL5 inhibition as adjunctive therapy with antibiotics in severe bacterial pneumonia may help reduce excessive inflammation and preserve lung barrier function.
{"title":"Neutrophil-chemoattractant CXCL5 increases lung barrier permeability in acute lung injury","authors":"Sarah Berger , Cengiz Goekeri , Peter Pennitz , Birgitt Gutbier , Laura Michalick , Karen Hoffmann , Elena Lopez-Rodriguez , Vladimir Gluhovic , Sandra-Maria Wienhold , Ulrike Behrendt , Alexander Taylor , Kristina Dietert , Holger Kirsten , Sandra Kunder , Kristina Mueller , Markus Weigel , Torsten Hain , Sarah M. Volkers , Sebastian Weis , Achim D. Gruber , Geraldine Nouailles","doi":"10.1016/j.mucimm.2025.10.003","DOIUrl":"10.1016/j.mucimm.2025.10.003","url":null,"abstract":"<div><div>Acute lung injury is a common complication of pneumonia, with disease severity linked to inflammatory cell recruitment and lung barrier dysfunction. In this study, we investigate the role of neutrophil-chemoattractant CXCL5 in lung barrier function and inflammation.</div><div>We examined CXCL5 in patients with severe pneumonia and in <em>in vitro</em> and <em>in vivo</em> models of acute lung injury. Pneumococcal infection and mechanical ventilation triggered CXCL5 release in both humans and mice. In <em>Cxcl5</em>-deficient mice, the alveolar-epithelial barrier remained intact despite acute lung injury, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial cells of <em>Cxcl5</em>-deficient mice. Consistently, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells.</div><div>Beyond its known role in neutrophil recruitment, CXCL5 independently increases alveolar-epithelial barrier permeability. Therefore, targeting CXCL5 inhibition as adjunctive therapy with antibiotics in severe bacterial pneumonia may help reduce excessive inflammation and preserve lung barrier function.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 6","pages":"Pages 1438-1449"},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275260","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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