Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2025.01.009
Yuki Oya, Shunsuke Kimura, Maho Uemura, Yumiko Fujimura, Koji Hase
The ocular mucosal surface regularly encounters external materials in the air and tear fluids. Microfold (M) cells, specialized epithelial cells for antigen uptake, are present in tear duct-associated lymphoid tissue (TALT) within the nasolacrimal sac; however, their immunological significance is unclear. We generated Krt5-Cre Tnfrsf11aflox/flox mice, which lack functional M cells in the TALT, as evidenced by the absence of M-cell markers and reduced nanoparticle uptake. M cell deficiency resulted in fewer T follicular helper (Tfh) and germinal center (GC) B cells in the TALT under steady-state conditions. Upon induction of allergic conjunctivitis, control mice exhibited itching and increased Tfh and immunoglobulin E (IgE+) GC B cells in the TALT. However, M cell-deficient mice showed ameliorated allergic symptoms with fewer Tfh and IgE+ GC B cells. These findings suggest that M cells in TALT contribute to ocular surface immunosurveillance, whereas, upon allergen exposure, they play a critical role in the development of allergic conjunctivitis.
{"title":"Tear duct M cells exacerbate allergic conjunctivitis by facilitating germinal-center reactions.","authors":"Yuki Oya, Shunsuke Kimura, Maho Uemura, Yumiko Fujimura, Koji Hase","doi":"10.1016/j.mucimm.2025.01.009","DOIUrl":"10.1016/j.mucimm.2025.01.009","url":null,"abstract":"<p><p>The ocular mucosal surface regularly encounters external materials in the air and tear fluids. Microfold (M) cells, specialized epithelial cells for antigen uptake, are present in tear duct-associated lymphoid tissue (TALT) within the nasolacrimal sac; however, their immunological significance is unclear. We generated Krt5-Cre Tnfrsf11a<sup>flox/flox</sup> mice, which lack functional M cells in the TALT, as evidenced by the absence of M-cell markers and reduced nanoparticle uptake. M cell deficiency resulted in fewer T follicular helper (Tfh) and germinal center (GC) B cells in the TALT under steady-state conditions. Upon induction of allergic conjunctivitis, control mice exhibited itching and increased Tfh and immunoglobulin E (IgE<sup>+</sup>) GC B cells in the TALT. However, M cell-deficient mice showed ameliorated allergic symptoms with fewer Tfh and IgE<sup>+</sup> GC B cells. These findings suggest that M cells in TALT contribute to ocular surface immunosurveillance, whereas, upon allergen exposure, they play a critical role in the development of allergic conjunctivitis.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122946","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 : 2025-02-01DOI: 10.1016/j.mucimm.2024.09.005
Maria-Bernadette Madel , Lidia Ibáñez , Thomas Ciucci , Julia Halper , Antoine Boutin , Ghada Beldi , Alice C. Lavanant , Henri-Jean Garchon , Matthieu Rouleau , Christopher G. Mueller , Laurent Peyrin-Biroulet , David Moulin , Claudine Blin-Wakkach , Abdelilah Wakkach
Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn’s disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.
{"title":"Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner","authors":"Maria-Bernadette Madel , Lidia Ibáñez , Thomas Ciucci , Julia Halper , Antoine Boutin , Ghada Beldi , Alice C. Lavanant , Henri-Jean Garchon , Matthieu Rouleau , Christopher G. Mueller , Laurent Peyrin-Biroulet , David Moulin , Claudine Blin-Wakkach , Abdelilah Wakkach","doi":"10.1016/j.mucimm.2024.09.005","DOIUrl":"10.1016/j.mucimm.2024.09.005","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn’s disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 90-104"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.09.001
Luke B. Roberts , Joana F. Neves , Dave C.H. Lee , Sara Valpione , Roser Tachó-Piñot , Jane K. Howard , Matthew R. Hepworth , Graham M. Lord
The transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline Mir142 deletion alters intestinal ILC compositions, resulting in the absence of T-bet+ populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6+ LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, Mir142−/− mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer’s patches. Conditional deletion of Mir142 in ILC3s (RorcΔMir142) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTi-like ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of Mir142 in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity.
{"title":"MicroRNA-142 regulates gut associated lymphoid tissues and group 3 innate lymphoid cells","authors":"Luke B. Roberts , Joana F. Neves , Dave C.H. Lee , Sara Valpione , Roser Tachó-Piñot , Jane K. Howard , Matthew R. Hepworth , Graham M. Lord","doi":"10.1016/j.mucimm.2024.09.001","DOIUrl":"10.1016/j.mucimm.2024.09.001","url":null,"abstract":"<div><div>The transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline <em>Mir142</em> deletion alters intestinal ILC compositions, resulting in the absence of T-bet<sup>+</sup> populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6<sup>+</sup> LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, <em>Mir142<sup>−/−</sup></em> mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer’s patches. Conditional deletion of <em>Mir142</em> in ILC3s (<em>Rorc</em><sup>Δ</sup><em><sup>Mir142</sup></em>) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTi-like ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of <em>Mir142</em> in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 39-52"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.10.003
Fabian Bick , Christophe Blanchetot , Bart N. Lambrecht , Martijn J. Schuijs
While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining TH9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9′s cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.
{"title":"A reappraisal of IL-9 in inflammation and cancer","authors":"Fabian Bick , Christophe Blanchetot , Bart N. Lambrecht , Martijn J. Schuijs","doi":"10.1016/j.mucimm.2024.10.003","DOIUrl":"10.1016/j.mucimm.2024.10.003","url":null,"abstract":"<div><div>While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining T<sub>H</sub>9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9′s cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 1-15"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.11.009
Laura Matarazzo , Charlotte Costa , Rémi Porte , Jean-Michel Saliou , Martin Figeac , Fabien Delahaye , Amélie Bonnefond , Benoit Kloeckner , Aymeric Silvin , Florent Ginhoux , Christelle Faveeuw , Mara Baldry , Christophe Carnoy , Jean-Claude Sirard
Host-directed therapy, using nasal administration of the Toll-like receptor 5 agonist flagellin in combination with antibiotics, has proven effective against pneumococcal pneumonia. In this study, we investigated the immune mechanisms underlying the therapy-induced protective effects. Transcriptomic analysis of lung tissue during infection revealed that flagellin not only enhanced pathways associated with myeloid cell infiltration into the airways and antimicrobial functions, but also promoted the early and transient mobilization of neutrophils and inflammatory monocytes. Neutrophils were identified as crucial for the protective effects of flagellin. The adjunct activity of flagellin correlated with the increased recruitment of neutrophils into airways, their localization at the periphery of bronchi, alveoli, and lung vessels, along with alterations in phagocytic activity. Clustering analysis identified seven neutrophil subsets; notably, flagellin adjunct treatment expanded clusters involved in recruitment and antibacterial activity, and primed augmented functionality. In conclusion, this study highlights specific neutrophil subsets as a promising target for host-directed therapy in infection.
{"title":"Neutrophil subsets enhance the efficacy of host-directed therapy in pneumococcal pneumonia","authors":"Laura Matarazzo , Charlotte Costa , Rémi Porte , Jean-Michel Saliou , Martin Figeac , Fabien Delahaye , Amélie Bonnefond , Benoit Kloeckner , Aymeric Silvin , Florent Ginhoux , Christelle Faveeuw , Mara Baldry , Christophe Carnoy , Jean-Claude Sirard","doi":"10.1016/j.mucimm.2024.11.009","DOIUrl":"10.1016/j.mucimm.2024.11.009","url":null,"abstract":"<div><div>Host-directed therapy, using nasal administration of the Toll-like receptor 5 agonist flagellin in combination with antibiotics, has proven effective against pneumococcal pneumonia. In this study, we investigated the immune mechanisms underlying the therapy-induced protective effects. Transcriptomic analysis of lung tissue during infection revealed that flagellin not only enhanced pathways associated with myeloid cell infiltration into the airways and antimicrobial functions, but also promoted the early and transient mobilization of neutrophils and inflammatory monocytes. Neutrophils were identified as crucial for the protective effects of flagellin. The adjunct activity of flagellin correlated with the increased recruitment of neutrophils into airways, their localization at the periphery of bronchi, alveoli, and lung vessels, along with alterations in phagocytic activity. Clustering analysis identified seven neutrophil subsets; notably, flagellin adjunct treatment expanded clusters involved in recruitment and antibacterial activity, and primed augmented functionality. In conclusion, this study highlights specific neutrophil subsets as a promising target for host-directed therapy in infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 257-268"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.12.003
Eduardo J. Villablanca
In complex organisms, functional units must interact cohesively to maintain homeostasis, especially within mucosal barriers that house diverse, specialized cell exposed to constant environmental challenges. Understanding how homeostasis at mucosal barriers is maintained and how its disruption can lead to autoimmune diseases or cancer, requires a holistic view. Although omics approaches and systems immunology have become powerful tools, they are not without limitations; interpretations may reflect researchers’ assumptions, even if other explanations exist. In this perspective, I propose that applying game theory concepts to mucosal immunology could help interpret complex data, offering fresh perspectives and supporting the exploration of alternative scenarios. By framing the mucosal immune system as a network of strategic interactions with multiple possible outcomes, game theory, which analyzes strategic interactions and decision-making processes, could illuminate novel cell types and functions, cell interactions, and responses to pathogens and commensals, leading to a more comprehensive understanding of immune homeostasis and diseases. In addition, game theory might encourage researchers to consider a broader range of possibilities, reduce the risk of myopic thinking, and ultimately enable a more refined and comprehensive understanding of the complexity of the immune system at mucosal barriers. This perspective aims to introduce game theory as a complementary framework for mucosal immunologists, encouraging them to incorporate these concepts into data interpretation and system modeling.
{"title":"Organismal mucosal immunology: A perspective through the eyes of game theory","authors":"Eduardo J. Villablanca","doi":"10.1016/j.mucimm.2024.12.003","DOIUrl":"10.1016/j.mucimm.2024.12.003","url":null,"abstract":"<div><div>In complex organisms, functional units must interact cohesively to maintain homeostasis, especially within mucosal barriers that house diverse, specialized cell exposed to constant environmental challenges. Understanding how homeostasis at mucosal barriers is maintained and how its disruption can lead to autoimmune diseases or cancer, requires a holistic view. Although omics approaches and systems immunology have become powerful tools, they are not without limitations; interpretations may reflect researchers’ assumptions, even if other explanations exist. In this perspective, I propose that applying game theory concepts to mucosal immunology could help interpret complex data, offering fresh perspectives and supporting the exploration of alternative scenarios. By framing the mucosal immune system as a network of strategic interactions with multiple possible outcomes, game theory, which analyzes strategic interactions and decision-making processes, could illuminate novel cell types and functions, cell interactions, and responses to pathogens and commensals, leading to a more comprehensive understanding of immune homeostasis and diseases. In addition, game theory might encourage researchers to consider a broader range of possibilities, reduce the risk of myopic thinking, and ultimately enable a more refined and comprehensive understanding of the complexity of the immune system at mucosal barriers. This perspective aims to introduce game theory as a complementary framework for mucosal immunologists, encouraging them to incorporate these concepts into data interpretation and system modeling.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 16-25"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2025.01.001
Yunxia Xue , Pengyang Xu , Yu Hu , Sijing Liu , Ruyu Yan , Shutong Liu , Yan Li , Jun Liu , Ting Fu , Zhijie Li
{"title":"Corrigendum to “Stress systems exacerbate the inflammatory response after corneal abrasion in sleep-deprived mice via the IL-17 signaling pathway” [Mucosal Immunol. 17(3) (2024) 323–345]","authors":"Yunxia Xue , Pengyang Xu , Yu Hu , Sijing Liu , Ruyu Yan , Shutong Liu , Yan Li , Jun Liu , Ting Fu , Zhijie Li","doi":"10.1016/j.mucimm.2025.01.001","DOIUrl":"10.1016/j.mucimm.2025.01.001","url":null,"abstract":"","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Page 269"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.11.004
Meret Tuor , Mark H.T. Stappers , Alice Desgardin , Fiorella Ruchti , Florian Sparber , Selinda J. Orr , Neil A.R. Gow , Salomé LeibundGut-Landmann
The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo. In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.
{"title":"Card9 and MyD88 differentially regulate Th17 immunity to the commensal yeast Malassezia in the murine skin","authors":"Meret Tuor , Mark H.T. Stappers , Alice Desgardin , Fiorella Ruchti , Florian Sparber , Selinda J. Orr , Neil A.R. Gow , Salomé LeibundGut-Landmann","doi":"10.1016/j.mucimm.2024.11.004","DOIUrl":"10.1016/j.mucimm.2024.11.004","url":null,"abstract":"<div><div>The fungal community of the skin microbiome is dominated by a single genus, <em>Malassezia</em>. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to <em>Malassezia</em> remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of <em>Malassezia</em> and induce dendritic cell activation <em>in vitro</em>, while only Dectin-2 is required for Th17 activation during experimental skin colonization <em>in vivo.</em> In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 205-219"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.10.002
Gesa J. Albers , Christina Michalaki , Patricia P. Ogger , Amy F. Lloyd , Benjamin Causton , Simone A. Walker , Anna Caldwell , John M. Halket , Linda V. Sinclair , Sarah H. Forde , Cormac McCarthy , Timothy S.C. Hinks , Clare M. Lloyd , Adam J. Byrne
The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.
肺是一个动态的微环境，气道巨噬细胞（AMs）是驻肺的主要巨噬细胞。巨噬细胞决定着组织稳态和免疫激活之间的平衡，因此具有相互矛盾的功能，既能维持耐受性和组织稳态，又能引发强烈的炎症反应。新的证据强调了巨噬细胞功能与细胞新陈代谢之间的联系。然而，这些过程在组织驻留的特化巨噬细胞群（如在呼吸道中发现的巨噬细胞群）中的功能重要性仍未得到充分阐明。在这里，我们揭示了糖酵解是巨噬细胞的一个基本途径，它同时调节着肺的稳态和对吸入过敏原的反应。利用体内巨噬细胞特异性靶向和多组学方法，我们确定了AMs中的糖酵解活性是在体内平衡过程中抑制2型（T2）免疫所必需的。暴露于包括屋尘螨（HDM）在内的一系列常见空气过敏原会促进AM糖酵解，此外，AM特异性糖酵解抑制会改变气道炎症和HDM驱动的体内气道代谢适应。此外，与未致敏的哮喘对照组相比，过敏原致敏的哮喘患者的气道代谢发生了深刻变化。最后，我们发现过敏原驱动的小鼠 AM 糖酵解作用依赖于 TLR2。因此，我们的研究结果表明，AM 中的糖酵解、AM 介导的体内平衡过程和肺部的 T2 免疫反应之间存在直接关系。这些数据表明，糖酵解对 AM 的可塑性至关重要。根据不同的免疫环境，AM-糖酵解需要发挥稳态活性，但一旦被过敏原激活，AM-糖酵解就会影响炎症反应。因此，精确调节AMs中的糖酵解活性对于保持肺稳态和调节气道炎症至关重要。
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Pub Date : 2025-02-01DOI: 10.1016/j.mucimm.2024.11.002
Nai-Wen Fan , Man Yu , Shudan Wang , Tomas Blanco , Zala Luznik , Sunil K. Chauhan , Veena Viswanath , Daniel Gil , Katherine Held , Yihe Chen , Reza Dana
There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II+CD11b+ cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.Rag1-/- mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.
干眼症（DED）是一种由 T 细胞介导的慢性、炎症性眼表疾病，有效治疗干眼症的需求尚未得到满足。鉴于非神经元肾上腺素能系统在调节 T 细胞反应方面的潜力，我们在此研究了特异性α2 肾上腺素能受体激动剂（AGN-762，对α2B/2C 受体亚型具有选择性）在 DED 小鼠模型中的疗效及其潜在机制。实验性 DED 在疾病诱导期或发病后通过口服 AGN-762 治疗，结果显示病情持续改善，眼表组织中 DED 致病细胞因子的表达减少，角膜 MHC-II+CD11b+ 细胞和淋巴 Th17 细胞减少，调节性 T 细胞（Treg）的功能增强。用 AGN-762 体外培养 DED 衍生的效应 T 辅助细胞 (Teff) 未能抑制 Th17 反应，而用 AGN-762 培养 DED-Treg 则增强了 Treg 的抑制功能及其 IL-10 的产生。AGN-762预处理过的DED-Treg在共生B6.Rag1-/-小鼠中的接种转移能有效抑制DED Teff介导的疾病和Th17反应，而IL-10的中和作用会取消这种效果。总之，我们的研究结果表明，α2B/2C肾上腺素能受体激动能通过增强Treg产生IL-10从而恢复其免疫调节功能，从而有效地改善DED的持续性角膜上皮病变。
{"title":"Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function","authors":"Nai-Wen Fan , Man Yu , Shudan Wang , Tomas Blanco , Zala Luznik , Sunil K. Chauhan , Veena Viswanath , Daniel Gil , Katherine Held , Yihe Chen , Reza Dana","doi":"10.1016/j.mucimm.2024.11.002","DOIUrl":"10.1016/j.mucimm.2024.11.002","url":null,"abstract":"<div><div>There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II<sup>+</sup>CD11b<sup>+</sup> cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.<em>Rag1<sup>-/-</sup></em> mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 176-187"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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