Pub Date : 2026-02-01Epub Date: 2025-10-26DOI: 10.1016/j.mucimm.2025.10.009
Martina Palatella , Friederike Kruse , Honglei Ji , Alina K. Loriani Fard , Maike Becker , Carolin Daniel , Maria Rohm , Jochen Huehn
The immune balance in mucosal tissues depends on a delicate interplay between inflammatory T helper 17 (Th17) cells and immunosuppressive regulatory T cells (Tregs). But what happens when this balance is disturbed? In this study, we uncovered a critical role for Acyl-CoA synthetase bubblegum family member 1 (Acsbg1) in shaping Th17 and Treg dynamics. Using Acsbg1-deficient mice, we show that while its absence does not disrupt homeostasis under steady-state conditions, it significantly alters Treg populations, particularly in gut-associated tissues. Under high-fat diet-induced metabolic stress, Acsbg1-deficient mice display mild metabolic changes but maintain systemic immune and metabolic function, indicating that Acsbg1 is dispensable for metabolic adaptation in vivo. However, upon infection with Citrobacter rodentium, these mice exhibit excessive Th1/Th17-driven inflammation and impaired resolution, accompanied by a strong reduction in IL-10-producing and ST2+ Treg subsets. The impact is even more striking in an adoptive transfer colitis model, where Acsbg1-deficient Tregs fail to control inflammation, resulting in severe colitis and tissue damage. Our findings identify Acsbg1 as a key regulator of ST2+ Treg function and a central player in mucosal immune homeostasis, highlighting its potential as a therapeutic target for inflammatory bowel disease and colorectal cancer.
{"title":"Acsbg1 maintains intestinal immune homeostasis and controls inflammation by regulating ST2+ Tregs","authors":"Martina Palatella , Friederike Kruse , Honglei Ji , Alina K. Loriani Fard , Maike Becker , Carolin Daniel , Maria Rohm , Jochen Huehn","doi":"10.1016/j.mucimm.2025.10.009","DOIUrl":"10.1016/j.mucimm.2025.10.009","url":null,"abstract":"<div><div>The immune balance in mucosal tissues depends on a delicate interplay between inflammatory T helper 17 (Th17) cells and immunosuppressive regulatory T cells (Tregs). But what happens when this balance is disturbed? In this study, we uncovered a critical role for Acyl-CoA synthetase bubblegum family member 1 (<em>Acsbg1</em>) in shaping Th17 and Treg dynamics. Using <em>Acsbg1</em>-deficient mice, we show that while its absence does not disrupt homeostasis under steady-state conditions, it significantly alters Treg populations, particularly in gut-associated tissues. Under high-fat diet-induced metabolic stress, <em>Acsbg1</em>-deficient mice display mild metabolic changes but maintain systemic immune and metabolic function, indicating that Acsbg1 is dispensable for metabolic adaptation <em>in vivo</em>. However, upon infection with <em>Citrobacter rodentium</em>, these mice exhibit excessive Th1/Th17-driven inflammation and impaired resolution, accompanied by a strong reduction in IL-10-producing and ST2<sup>+</sup> Treg subsets. The impact is even more striking in an adoptive transfer colitis model, where <em>Acsbg1</em>-deficient Tregs fail to control inflammation, resulting in severe colitis and tissue damage. Our findings identify Acsbg1 as a key regulator of ST2<sup>+</sup> Treg function and a central player in mucosal immune homeostasis, highlighting its potential as a therapeutic target for inflammatory bowel disease and colorectal cancer.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1526-1537"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391525","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 : 2026-02-01Epub Date: 2025-11-10DOI: 10.1016/j.mucimm.2025.11.003
Chongshan Yuan , Yun Zhang , Yuhong He , Nier Su , Chong Peng , Xiaoyu Hu , Caijun Zhao , Yunhe Fu , Hai Li , Jun Wang , Yue Zhang
Endometrial injury triggers inflammation responses, and persistent inflammation is a recognized cause of infertility. Emerging evidence underscores the critical role of the vagus nerve in modulating immunity. Although vagotomy is known to induce systemic inflammation, the specific mechanism by which the vagus nerve regulates uterine health is still unclear. In this study, we employed a vagotomy model to investigate the therapeutic potential of pantothenic acid in alleviating endometrial injury. Our results showed that left cervical vagotomy reduces the integrity of the endometrium and the expression of barrier proteins such as Claudin-3, Occludin, and ZO-1. Vagotomy increases the levels of inflammatory cytokines (TNF-α and IL-1β) and LPS in uterine tissue and serum through the NF-κB signaling pathway. Furthermore, we found that vagotomy promotes ferroptosis by decreasing the protein expression of SLC7A11 and GPX4 and increasing the level of COX2. Vagotomy significantly altered the composition of the uterine microbiota, characterized by a significant enrichment of Rodentibacter and a depletion of Vagococcus and Acetobacter. Next, we found that vagotomy can cause an increase in serum levels of lysoPE 20:4, antipyrine, and lysoPE18:2, as well as a decrease in levels of hexanoyl-L-Carnitine and pantothenic acid. When pantothenic acid was supplemented, the endometrial injury caused by vagotomy was reversed. Pantothenic acid increased the expression of barrier proteins in the endometrium and reduced the content of inflammatory cytokines in uterine tissue and serum of mice. At the same time, pantothenic acid also reversed the degree of ferroptosis induced by vagotomy in uterine tissue and serum. Our study demonstrates that vagotomy disrupts the endometrial microbiota and promotes endometrium injury and the markers of ferroptosis via the NF-κB pathway. Pantothenic acid supplementation alleviates vagus nerve-mediated endometrial injury. These results highlight that vagus nerve regulation of uterine health through pantothenic acid is a promising strategy.
{"title":"Pantothenic acid alleviates endometrial injury induced by vagotomy in mice","authors":"Chongshan Yuan , Yun Zhang , Yuhong He , Nier Su , Chong Peng , Xiaoyu Hu , Caijun Zhao , Yunhe Fu , Hai Li , Jun Wang , Yue Zhang","doi":"10.1016/j.mucimm.2025.11.003","DOIUrl":"10.1016/j.mucimm.2025.11.003","url":null,"abstract":"<div><div>Endometrial injury triggers inflammation responses, and persistent inflammation is a recognized cause of infertility. Emerging evidence underscores the critical role of the vagus nerve in modulating immunity. Although vagotomy is known to induce systemic inflammation, the specific mechanism by which the vagus nerve regulates uterine health is still unclear. In this study, we employed a vagotomy model to investigate the therapeutic potential of pantothenic acid in alleviating endometrial injury. Our results showed that left cervical vagotomy reduces the integrity of the endometrium and the expression of barrier proteins such as Claudin-3, Occludin, and ZO-1. Vagotomy increases the levels of inflammatory cytokines (TNF-α and IL-1β) and LPS in uterine tissue and serum through the NF-κB signaling pathway. Furthermore, we found that vagotomy promotes ferroptosis by decreasing the protein expression of SLC7A11 and GPX4 and increasing the level of COX2. Vagotomy significantly altered the<!--> <!-->composition<!--> <!-->of the uterine microbiota,<!--> <!-->characterized by a significant enrichment of <em>Rodentibacter</em> and a depletion of <em>Vagococcus</em> and <em>Acetobacter</em>. Next, we found that vagotomy can cause an increase in serum levels of lysoPE 20:4, antipyrine, and lysoPE18:2, as well as a decrease in levels of hexanoyl-L-Carnitine and pantothenic acid. When pantothenic acid was supplemented, the endometrial injury caused by vagotomy was reversed. Pantothenic acid increased the expression of barrier proteins in the endometrium and reduced the content of inflammatory cytokines in uterine tissue and serum of mice. At the same time, pantothenic acid also reversed the degree of ferroptosis induced by vagotomy in uterine tissue and serum. Our study demonstrates that vagotomy disrupts the endometrial microbiota and promotes endometrium injury and the markers of ferroptosis <em>via</em> the NF-κB pathway. Pantothenic acid supplementation alleviates vagus nerve-mediated endometrial injury. These results highlight that vagus nerve regulation of uterine health through pantothenic acid is a promising strategy.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1573-1586"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145505582","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 : 2026-02-01Epub Date: 2025-11-17DOI: 10.1016/j.mucimm.2025.11.008
Daan K.J. Pieren , Aleix Benítez-Martínez , Vicente Descalzo , Maider Arando , Patricia Álvarez-López , Jorge N. Garcia-Perez , Núria Massana , Júlia Castellón , Yannick Hoyos-Mallecot , Daniel Alvárez-Sierra , Sergi Cantenys-Molina , Clara Ramírez-Serra , Nuria Laia Rodriguez , Laura Mañalich-Barrachina , Cristina Centeno-Mediavilla , Josep Castellví , Vicenç Falcó , María J. Buzón , Meritxell Genescà
The mucosal immune system plays a fundamental role in maintaining microbial balance. Microbial imbalance in the female genital tract increases the risk for adverse health outcomes in women and may increase susceptibility to local infections. Myeloid-derived suppressor cells (MDSCs) remain understudied in the context of female genital tract conditions. Here we show that frequency of polymorphonuclear (PMN-) MDSCs increased in the cervical mucosa of women with Chlamydia trachomatis infection, bacterial vaginosis, or with a coinfection, but not in women with human papillomavirus infection. Mucosal PMN-MDSC frequencies correlated with mucosal IL-1β in C. trachomatis patients and ex vivo exposure of cervical tissue to C. trachomatis elevated both PMN-MDSC frequencies and IL-1β secretion. Likewise, exposure of cervical tissue to cervicovaginal lavage fluid from C. trachomatis and bacterial vaginosis patients also enhanced PMN-MDSC frequencies. Lastly, cervical MDSCs expressed suppressive mediators and functionally suppressed cytotoxic T-cell responses. Our study identifies IL-1β–stimulated PMN-MDSCs as immunosuppressive mediators in female genital tract infections, potentially modulating susceptibility to local secondary infections.
{"title":"Cervical mucosal inflammation expands functional polymorphonuclear myeloid-derived suppressor cells","authors":"Daan K.J. Pieren , Aleix Benítez-Martínez , Vicente Descalzo , Maider Arando , Patricia Álvarez-López , Jorge N. Garcia-Perez , Núria Massana , Júlia Castellón , Yannick Hoyos-Mallecot , Daniel Alvárez-Sierra , Sergi Cantenys-Molina , Clara Ramírez-Serra , Nuria Laia Rodriguez , Laura Mañalich-Barrachina , Cristina Centeno-Mediavilla , Josep Castellví , Vicenç Falcó , María J. Buzón , Meritxell Genescà","doi":"10.1016/j.mucimm.2025.11.008","DOIUrl":"10.1016/j.mucimm.2025.11.008","url":null,"abstract":"<div><div>The mucosal immune system plays a fundamental role in maintaining microbial balance. Microbial imbalance in the female genital tract increases the risk for adverse health outcomes in women and may increase susceptibility to local infections. Myeloid-derived suppressor cells (MDSCs) remain understudied in the context of female genital tract conditions. Here we show that frequency of polymorphonuclear (PMN-) MDSCs increased in the cervical mucosa of women with <em>Chlamydia trachomatis</em> infection, bacterial vaginosis, or with a coinfection, but not in women with human papillomavirus infection. Mucosal PMN-MDSC frequencies correlated with mucosal IL-1β in <em>C. trachomatis</em> patients and e<em>x vivo</em> exposure of cervical tissue to <em>C. trachomatis</em> elevated both PMN-MDSC frequencies and IL-1β secretion. Likewise, exposure of cervical tissue to cervicovaginal lavage fluid from <em>C. trachomatis</em> and bacterial vaginosis patients also enhanced PMN-MDSC frequencies. Lastly, cervical MDSCs expressed suppressive mediators and functionally suppressed cytotoxic T-cell responses. Our study identifies IL-1β–stimulated PMN-MDSCs as immunosuppressive mediators in female genital tract infections, potentially modulating susceptibility to local secondary infections.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1636-1649"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557188","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 : 2026-02-01Epub Date: 2025-11-19DOI: 10.1016/j.mucimm.2025.11.004
Emily L. Plumpton , Stefano A.P. Colombo , Matthew Steward , Sheila L. Brown , Saba Khan , Gaël Tavernier , Helen Francis , Hazel Platt , Tracy Hussell , William G.C. Horsnell , David W. Denning , Robert Niven , Angela Simpson , Andrew S. MacDonald , Peter C. Cook
Airborne fungi are potent inducers of respiratory disease and cause the debilitating conditions severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). However, the immune cell types and the inflammatory airway environment that defines SAFS and ABPA patients is not extensively characterised. To address this, we recruited SAFS and ABPA patients, asthmatics without evidence of fungal sensitisation and healthy controls (n = 20 individuals per group). Immune cells were isolated from collected sputum and peripheral blood samples and immunophenotyping was performed via flow cytometry. By applying a machine learning approach to our dataset, we identify a critical association between CD4+ T cells, type 2 conventional dendritic cells, eosinophils, proinflammatory factors and severe respiratory disease. These complex immune signatures should be investigated further to improve the diagnostics and treatment of SAFS and ABPA.
{"title":"Activation status of airway immune cells is a defining feature of severe asthma, regardless of fungal sensitisation","authors":"Emily L. Plumpton , Stefano A.P. Colombo , Matthew Steward , Sheila L. Brown , Saba Khan , Gaël Tavernier , Helen Francis , Hazel Platt , Tracy Hussell , William G.C. Horsnell , David W. Denning , Robert Niven , Angela Simpson , Andrew S. MacDonald , Peter C. Cook","doi":"10.1016/j.mucimm.2025.11.004","DOIUrl":"10.1016/j.mucimm.2025.11.004","url":null,"abstract":"<div><div>Airborne fungi are potent inducers of respiratory disease and cause the debilitating conditions severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). However, the immune cell types and the inflammatory airway environment that defines SAFS and ABPA patients is not extensively characterised. To address this, we recruited SAFS and ABPA patients, asthmatics without evidence of fungal sensitisation and healthy controls (n = 20 individuals per group). Immune cells were isolated from collected sputum and peripheral blood samples and immunophenotyping was performed via flow cytometry. By applying a machine learning approach to our dataset, we identify a critical association between CD4<sup>+</sup> T cells, type 2 conventional dendritic cells, eosinophils, proinflammatory factors and severe respiratory disease. These complex immune signatures should be investigated further to improve the diagnostics and treatment of SAFS and ABPA.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1587-1598"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573870","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 : 2026-02-01Epub Date: 2025-10-19DOI: 10.1016/j.mucimm.2025.10.007
Sara Dylgjeri , Ewelina M. Bartoszek , Petr Hruz , Hassan Melhem , Jan Hendrik Niess
Xenobiotics and environmental factors implicated in inflammatory bowel disease (IBD) are metabolized by cytochrome P450 enzymes. Cyp2s1, an orphan member of this family, is highly expressed in the intestine, yet its role remains unclear. Here, we investigated the function of Cyp2s1 in intestinal homeostasis and inflammation by combining untargeted metabolomics, microbiome sequencing, colitis mouse models, and IBD patient biopsies. We observed markedly reduced Cyp2s1 expression in patients with active IBD and in multiple colitis models. Single-cell RNA sequencing identified abundant Cyp2s1 expression in the intestinal epithelium. Importantly, the AhR agonist, 6-Formylindolo[3,2-b]carbazole (FICZ) robustly induced Cyp2s1 expression in mouse colon organoids and Caco-2 cells. Mechanistically, metabolomic analysis of intestinal epithelial cells and feces from mice overexpressing or lacking Cyp2s1 revealed altered metabolite profiles. The SCENITH assay further confirmed disrupted fatty acid oxidation capacity in colonocytes of Cyp2s1-transgenic mice. Moreover, shotgun microbiome sequencing revealed reduced microbial richness and expansion of A. muciniphila in Cyp2s1-overexpressing mice. Consequently, upon DSS challenge, these mice developed exacerbated colitis symptoms compared to controls. Our findings identify Cyp2s1 as a novel AhR-inducible gene critical for modulating the intestinal metabolome and microbiome, suggesting that targeting AhR activity or Cyp2s1 itself may offer therapeutic strategies for IBD.
{"title":"Cytochrome P450 Cyp2s1 regulation of the intestinal metabolome and microbiome","authors":"Sara Dylgjeri , Ewelina M. Bartoszek , Petr Hruz , Hassan Melhem , Jan Hendrik Niess","doi":"10.1016/j.mucimm.2025.10.007","DOIUrl":"10.1016/j.mucimm.2025.10.007","url":null,"abstract":"<div><div>Xenobiotics and environmental factors implicated in inflammatory bowel disease (IBD) are metabolized by cytochrome P450 enzymes. Cyp2s1, an orphan member of this family, is highly expressed in the intestine, yet its role remains unclear. Here, we investigated the function of Cyp2s1 in intestinal homeostasis and inflammation by combining untargeted metabolomics, microbiome sequencing, colitis mouse models, and IBD patient biopsies. We observed markedly reduced <em>Cyp2s1</em> expression in patients with active IBD and in multiple colitis models. Single-cell RNA sequencing identified abundant <em>Cyp2s1</em> expression in the intestinal epithelium. Importantly, the AhR agonist, 6-Formylindolo[3,2-b]carbazole (FICZ) robustly induced <em>Cyp2s1</em> expression in mouse colon organoids and Caco-2 cells. Mechanistically, metabolomic analysis of intestinal epithelial cells and feces from mice overexpressing or lacking Cyp2s1 revealed altered metabolite profiles. The SCENITH assay further confirmed disrupted fatty acid oxidation capacity in colonocytes of Cyp2s1-transgenic mice. Moreover, shotgun microbiome sequencing revealed reduced microbial richness and expansion of <em>A. muciniphila</em> in Cyp2s1-overexpressing mice. Consequently, upon DSS challenge, these mice developed exacerbated colitis symptoms compared to controls. Our findings identify Cyp2s1 as a novel AhR-inducible gene critical for modulating the intestinal metabolome and microbiome, suggesting that targeting AhR activity or Cyp2s1 itself may offer therapeutic strategies for IBD.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1496-1508"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346196","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 : 2026-02-01Epub Date: 2025-10-24DOI: 10.1016/j.mucimm.2025.10.008
Nabina Pun , Urszula M Cytlak , Dave Lee , Rita G Domingues , Eleanor J Cheadle , Duncan Forster , Clara Whiteley , Jamie Honeychurch , Kaye J Williams , Gerard J Graham , Matthew R Hepworth , Mark A Travis , Timothy M Illidge , Douglas P Dyer
Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to help regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood.
Following CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of innate immune cells. Deletion of C–C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation-induced toxicities, suggesting an important role for an innate immune cell population in limiting RT-mediated bowel damage.
Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C+ monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was found to be reduced in irradiated CCR2-/-, moreover the transfer of Ly6C+ monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities.
One Sentence Summary: CCR2-mediated monocyte recruitment protects against RT-induced intestinal toxicity via IL-17, highlighting a therapeutic target.
{"title":"CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity","authors":"Nabina Pun , Urszula M Cytlak , Dave Lee , Rita G Domingues , Eleanor J Cheadle , Duncan Forster , Clara Whiteley , Jamie Honeychurch , Kaye J Williams , Gerard J Graham , Matthew R Hepworth , Mark A Travis , Timothy M Illidge , Douglas P Dyer","doi":"10.1016/j.mucimm.2025.10.008","DOIUrl":"10.1016/j.mucimm.2025.10.008","url":null,"abstract":"<div><div>Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to help regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood.</div><div>Following CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of innate immune cells. Deletion of C–C chemokine receptor (<em>Ccr)1</em>, <em>Ccr2</em>, <em>Ccr3</em> and <em>Ccr5</em>, blocked recruitment and worsened radiation-induced toxicities, suggesting an important role for an innate immune cell population in limiting RT-mediated bowel damage.</div><div>Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C<sup>+</sup> monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was found to be reduced in irradiated CCR2<sup>-/-</sup>, moreover the transfer of Ly6C<sup>+</sup> monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities.</div><div><strong>One Sentence Summary:</strong> CCR2-mediated monocyte recruitment protects against RT-induced intestinal toxicity via IL-17, highlighting a therapeutic target.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1509-1525"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422214","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 : 2026-02-01Epub Date: 2025-11-12DOI: 10.1016/j.mucimm.2025.11.005
Oliver Brand , Sara Kirkham , Christopher Jagger , Matiss Ozols , Krishna Purohit , Ziyun Zhang , Rachel Lennon , Tracy Hussell , Alexander Eckersley
Identification of pathways preventing timely recovery from acute respiratory viral infection is under-studied but essential for long-term health. Using unbiased proteomics, we reveal an unexpected, reduction in lung basement membrane proteins 21 days after influenza infection when mice had symptomatically recovered. Basement membrane provides a critical scaffold for heterogeneous cell types and the proteins they secrete/express at the endothelial and epithelial barrier. Further peptide location fingerprinting analysis shows inherent structure-associated changes within core collagen IV and laminin components, particularly within the NC1 domains of collagen IV. Our results imply lingering damage to the basement membrane network despite symptomatic recovery from viral infection. Surprisingly, similar structure-associated changes in laminin and collagen IV components are also observed in non-infected, aged mice indicating that inflammation-driven basement membrane degeneration may contribute to tissue ageing. Interestingly, macrophages in regions deficient in basement membrane express collagen IV and laminin chains. Repair of the basement membrane should therefore be targeted to improve overall lung health.
Non-technical summary: Lung virus infection is a constant global threat, despite developments in vaccination and anti-viral treatments. We have a deep understanding of this inflammatory condition but less is known about the drivers of persistent problems, including fatigue and breathlessness as illustrated by “long COVID”. Here, we reveal a novel finding that a critical structure in the lung (the basement membrane) remains damaged after the influenza virus and symptoms have cleared. This structure supports a variety of cells and forms a barrier that lines the airspaces. It also regulates fluid and cell movement into these airspaces. Remarkably, we show that similar changes after virus infection are also evident in aged lungs, which implies that lung complications with age may be due to repeated inflammation. By identifying these persistent basement membrane changes, we provide an entirely novel area to target with new medicines to treat complications arising from viral infection.
{"title":"Lung basement membranes are compositionally and structurally altered following resolution of influenza infection","authors":"Oliver Brand , Sara Kirkham , Christopher Jagger , Matiss Ozols , Krishna Purohit , Ziyun Zhang , Rachel Lennon , Tracy Hussell , Alexander Eckersley","doi":"10.1016/j.mucimm.2025.11.005","DOIUrl":"10.1016/j.mucimm.2025.11.005","url":null,"abstract":"<div><div>Identification of pathways preventing timely recovery from acute respiratory viral infection is under-studied but essential for long-term health. Using unbiased proteomics, we reveal an unexpected, reduction in lung basement membrane proteins 21 days after influenza infection when mice had symptomatically recovered. Basement membrane provides a critical scaffold for heterogeneous cell types and the proteins they secrete/express at the endothelial and epithelial barrier. Further peptide location fingerprinting analysis shows inherent structure-associated changes within core collagen IV and laminin components, particularly within the NC1 domains of collagen IV. Our results imply lingering damage to the basement membrane network despite symptomatic recovery from viral infection. Surprisingly, similar structure-associated changes in laminin and collagen IV components are also observed in non-infected, aged mice indicating that inflammation-driven basement membrane degeneration may contribute to tissue ageing. Interestingly, macrophages in regions deficient in basement membrane express collagen IV and laminin chains. Repair of the basement membrane should therefore be targeted to improve overall lung health.</div><div><strong>Non-technical summary:</strong> Lung virus infection is a constant global threat, despite developments in vaccination and anti-viral treatments. We have a deep understanding of this inflammatory condition but less is known about the drivers of persistent problems, including fatigue and breathlessness as illustrated by “long COVID”. Here, we reveal a novel finding that a critical structure in the lung (the basement membrane) remains damaged after the influenza virus and symptoms have cleared. This structure supports a variety of cells and forms a barrier that lines the airspaces. It also regulates fluid and cell movement into these airspaces. Remarkably, we show that similar changes after virus infection are also evident in aged lungs, which implies that lung complications with age may be due to repeated inflammation. By identifying these persistent basement membrane changes, we provide an entirely novel area to target with new medicines to treat complications arising from viral infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 1","pages":"Pages 1599-1612"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513359","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 : 2026-01-30DOI: 10.1016/j.mucimm.2026.01.011
D Ai, L Kreyling, M A Battistone, M L Elizagaray, A Chen, S Bhushan, M Fijak, M Speckmann, G Michel, T Procida-Kowalski, M Bartkuhn, M Sprang, J U Mayer, A Meinhardt, C Pleuger
A finely tuned immune regulation within the epididymis and testis is essential for male reproductive health. This balance is especially critical in the epididymis, where sperm mature and ascending infections frequently disrupt homeostasis, resulting in regionally different immune responses and potential long-term fertility impairments. We previously demonstrated that the epididymis harbors a region-specific immunological scaffold, with CX3CR1+ macrophages as the most prominent epithelium-associated immune cell population. Here, we established a transgenic mouse model to selectively deplete these intraepithelial CX3CR1+ macrophages within the epididymis, resulting in focal epithelial damage and impaired sperm maturation processes essential for proper sperm functionality. Additionally, a mild reduction of the testicular macrophage pool resulted in transient disruptions in spermatogenesis and steroidogenesis. Although the macrophage niche was repopulated after depletion, the newly recruited cells displayed altered phenotypes consistent with persistent sperm alterations. Following infection with uropathogenic Escherichia coli (UPEC), macrophage-depleted mice exhibited exacerbated immune responses - particularly in normally protected proximal epididymal regions - with earlier onset and more severe tissue damage. Transcriptomic analysis revealed a failure to restrain inflammatory responses, especially in genes involved in immune regulation and antibacterial defense, accompanied by elevated immune cell infiltration in infected macrophage-depleted mice. Overall, our findings confirm a crucial role for CX3CR1+ macrophages in preserving epithelial integrity and modulating immune responses, supporting a stable tissue environment necessary for efficient organ function of both epididymis and testis.
{"title":"Depletion of CX3CR1<sup>+</sup> macrophages results in disrupted functionality and immune surveillance within epididymis and testis.","authors":"D Ai, L Kreyling, M A Battistone, M L Elizagaray, A Chen, S Bhushan, M Fijak, M Speckmann, G Michel, T Procida-Kowalski, M Bartkuhn, M Sprang, J U Mayer, A Meinhardt, C Pleuger","doi":"10.1016/j.mucimm.2026.01.011","DOIUrl":"10.1016/j.mucimm.2026.01.011","url":null,"abstract":"<p><p>A finely tuned immune regulation within the epididymis and testis is essential for male reproductive health. This balance is especially critical in the epididymis, where sperm mature and ascending infections frequently disrupt homeostasis, resulting in regionally different immune responses and potential long-term fertility impairments. We previously demonstrated that the epididymis harbors a region-specific immunological scaffold, with CX3CR1<sup>+</sup> macrophages as the most prominent epithelium-associated immune cell population. Here, we established a transgenic mouse model to selectively deplete these intraepithelial CX3CR1<sup>+</sup> macrophages within the epididymis, resulting in focal epithelial damage and impaired sperm maturation processes essential for proper sperm functionality. Additionally, a mild reduction of the testicular macrophage pool resulted in transient disruptions in spermatogenesis and steroidogenesis. Although the macrophage niche was repopulated after depletion, the newly recruited cells displayed altered phenotypes consistent with persistent sperm alterations. Following infection with uropathogenic Escherichia coli (UPEC), macrophage-depleted mice exhibited exacerbated immune responses - particularly in normally protected proximal epididymal regions - with earlier onset and more severe tissue damage. Transcriptomic analysis revealed a failure to restrain inflammatory responses, especially in genes involved in immune regulation and antibacterial defense, accompanied by elevated immune cell infiltration in infected macrophage-depleted mice. Overall, our findings confirm a crucial role for CX3CR1<sup>+</sup> macrophages in preserving epithelial integrity and modulating immune responses, supporting a stable tissue environment necessary for efficient organ function of both epididymis and testis.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100574","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 : 2026-01-27DOI: 10.1016/j.mucimm.2026.01.009
Quentin Lamy-Besnier, Seong-Eun G Kim, Thaís Vilela Rodrigues, Andrew T Gewirtz, Benoit Chassaing
The relationship between the intestinal microbiota and the mucosal immune system is a key determinant of health in that it plays a pivotal role in managing pathogens and avoiding chronic inflammatory diseases. Diet is a central mediator of this relationship, influencing microbiota composition as well as the function of gut bacteria and host cells. This article will review impacts of the myriad of dietary components capable of influencing the microbiota-immune system interrelationship. Such components include macronutrients, micronutrients, phytochemicals, fibers naturally present in traditional foods as well the array of food additives, including sweeteners, metals, fibers and emulsifiers that are widely incorporated into highly processed foods. We will discuss how presence and/or absence of these food components impacts health-related outcomes in mice, and mechanisms that might underlie these outcomes, including the role of the microbiota therein. We will also discuss emerging approaches to better understand the microbiota-immune system-diet interrelationship, including how they can be leveraged to improve health of humans.
{"title":"Gut trialogue: How diet influences mucosal immune system-microbiota interactions.","authors":"Quentin Lamy-Besnier, Seong-Eun G Kim, Thaís Vilela Rodrigues, Andrew T Gewirtz, Benoit Chassaing","doi":"10.1016/j.mucimm.2026.01.009","DOIUrl":"10.1016/j.mucimm.2026.01.009","url":null,"abstract":"<p><p>The relationship between the intestinal microbiota and the mucosal immune system is a key determinant of health in that it plays a pivotal role in managing pathogens and avoiding chronic inflammatory diseases. Diet is a central mediator of this relationship, influencing microbiota composition as well as the function of gut bacteria and host cells. This article will review impacts of the myriad of dietary components capable of influencing the microbiota-immune system interrelationship. Such components include macronutrients, micronutrients, phytochemicals, fibers naturally present in traditional foods as well the array of food additives, including sweeteners, metals, fibers and emulsifiers that are widely incorporated into highly processed foods. We will discuss how presence and/or absence of these food components impacts health-related outcomes in mice, and mechanisms that might underlie these outcomes, including the role of the microbiota therein. We will also discuss emerging approaches to better understand the microbiota-immune system-diet interrelationship, including how they can be leveraged to improve health of humans.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086438","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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