Mucosal Immunology最新文献

{"title":"Innate immunity of the lungs in homeostasis and disease","authors":"Peter A.A. Norris,&nbsp;Paul Kubes","doi":"10.1016/j.mucimm.2025.04.001","DOIUrl":"10.1016/j.mucimm.2025.04.001","url":null,"abstract":"<div><div>Humans breathe thousands of litres of non-sterile air each day containing bacteria, viruses, and fungi, as well as pollutants, allergens, and other particles. The continual exposure to foreign particles is juxtaposed with the vast surface area of the blood-air-barrier which becomes extremely thin to allow for efficient gas exchange. To prevent infection and injury, the healthy lung relies on a robust innate immune system to protect itself. Critically, this innate immune system must clear insults while maintaining immune tolerance and minimizing inflammation to avoid disrupting the lung’s vital gas exchange function. In this review, we discuss how the innate immune system protects the lung from its environment.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 757-769"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory chemokine receptors CCR1, CCR2, CCR3 and CCR5 are essential for an optimal T cell response to influenza","authors":"Marieke Pingen ,&nbsp;Catherine E. Hughes ,&nbsp;Laura Medina-Ruiz,&nbsp;Heather Mathie,&nbsp;Jennifer A. Barrie,&nbsp;Chris AH Hansell,&nbsp;Robin Bartolini,&nbsp;Megan KL MacLeod,&nbsp;Gerard J Graham","doi":"10.1016/j.mucimm.2025.05.005","DOIUrl":"10.1016/j.mucimm.2025.05.005","url":null,"abstract":"<div><div>Inflammatory chemokine receptors CCR1/2/3/5 (iCCRs) play an important role in the recruitment of immune cells involved in innate immune functions and orchestrating the adaptive immune response. Here we utilise an influenza A virus (IAV) challenge to investigate the combinatorial roles of the iCCRs in the anti-IAV immune response.</div><div>We did not observe any gross differences in infection-driven pathology in the absence of iCCRs. iCCR deletion resulted in decreased numbers of some antigen-presenting cell types in the lung (B cells, DC1s, monocytes and inflammatory macrophages), though cell numbers in the draining lymph node were not affected. Whilst the total number of T cells was similar in lungs of iCCR-deficient mice, the number of IAV-specific CD4 but not CD8 T cells in the lung was strongly reduced in the absence of iCCRs. Furthermore, fewer CD4, but not CD8, T cells produced IFN-γ.</div><div>This CD4 T cell phenotype persisted into the memory stage of infection, with fewer IAV-specific and IFN-γ⁺ CD4 but not CD8 T cells at 29 days post infection.</div><div>In conclusion, despite having limited impact on antigen-presenting cell migration between the lung and the draining lymph node, iCCR deletion is associated with an altered CD4 T cell response to IAV infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 951-957"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial single-cell analysis identifies placental villi structural and immune remodeling across gestation","authors":"Suganthinie Velagala ,&nbsp;Long Phan ,&nbsp;Chino Eke ,&nbsp;Analie Fernandes ,&nbsp;Tyler A. Rice ,&nbsp;Oluwabunmi Olaloye ,&nbsp;Liza Konnikova","doi":"10.1016/j.mucimm.2025.04.005","DOIUrl":"10.1016/j.mucimm.2025.04.005","url":null,"abstract":"<div><div>Pregnancies rely upon the balance between fetal and maternal immune systems. Employing imaging mass cytometry, this study creates a spatial map landscape to unravel the cellular dynamics within the placental villi (PV). Consistent with previous data we report structural remodeling in PV, highlighted by increased syncytial trophoblasts, vascular smooth muscle cells, and endothelial cells in term PV. Additionally, we identified that rare immune populations including dendritic cells, innate lymphoid cells, and myeloid-derived suppressor cells in mid-gestation were more abundant and activated than in term placentas, suggesting a potentially tolerogenic state. Conversely, various macrophage subtypes were increased and in combination with rare T-cells exhibited heightened activation markers, possibly indicating increased signaling in preparation for parturition. In mid-gestation, fibroblasts had increased interactions with trophoblasts, while term samples exhibited close adjacencies between trophoblasts, vascular smooth muscle cells, and macrophages. This study offers insights into the PV cellular composition changes between mid and full-term samples, providing a foundation for future studies to understand the mechanisms of preterm birth and other pregnancy complications.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 848-860"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PAD4 inhibition impacts immune responses in SARS-CoV-2 infection","authors":"Caio Santos Bonilha ,&nbsp;Flavio Protasio Veras ,&nbsp;Anderson dos Santos Ramos ,&nbsp;Giovanni Freitas Gomes ,&nbsp;Robertha Mariana Rodrigues Lemes ,&nbsp;Eurico Arruda ,&nbsp;José Carlos Alves-Filho ,&nbsp;Thiago Mattar Cunha ,&nbsp;Fernando Queiroz Cunha","doi":"10.1016/j.mucimm.2025.04.006","DOIUrl":"10.1016/j.mucimm.2025.04.006","url":null,"abstract":"<div><div>Protein arginine deiminase 4 (PAD4) has emerged as a potential therapeutic target for various diseases due to its role in promoting neutrophil extracellular trap (NET) formation. NETs, composed of DNA and antimicrobial proteins, serve as a defense mechanism against pathogens but can also drive lung injury, particularly in SARS-CoV-2 infection. In this study, we examined the effects of PAD4 inhibition on clinical outcomes and adaptive immunity within the context of SARS-CoV-2 infection. Our results show that PAD4 pharmacological inhibition reduced lung NET concentration and improved clinical outcomes, similar to treatment with recombinant human DNase (rhDNase), which degrades NET structure. However, in contrast to rhDNase, PAD4 targeting diminished virus-specific T cell responses by impairing dendritic cell antigen presentation and reducing IL-2 signaling by affecting its production by T cells. In line with these observations, PAD4 pharmacological inhibition diminished antigen-specific T cell responses in a model of lung inflammation. These findings highlight the importance of carefully evaluating PAD4 as a therapeutic target in COVID-19, given its potential to compromise adaptive immune responses crucial for fighting the virus.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 861-873"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory monocyte-derived amphiregulin mediates intestinal fibrosis in Crohn’s disease by activating PI3K/AKT","authors":"Shu Wang ,&nbsp;Lu Wang ,&nbsp;Junjie Lin ,&nbsp;Mingyuan Wang,&nbsp;Jiajia Li,&nbsp;Qiong Guo,&nbsp;Chunhua Jiao,&nbsp;Nana Tang,&nbsp;Jingjing Ma,&nbsp;Hongjie Zhang,&nbsp;Xiaojing Zhao","doi":"10.1016/j.mucimm.2025.05.008","DOIUrl":"10.1016/j.mucimm.2025.05.008","url":null,"abstract":"<div><div>Intestinal fibrosis is one of the most threatening complications of Crohn’s disease (CD). Although our previous study identified the profibrotic role of amphiregulin (AREG) in intestinal fibrosis, the underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanisms by which AREG mediates intestinal fibrosis. Specimens from stenotic and non-stenotic lesions in CD patients were collected, alongside normal specimens from individuals with intestinal diverticula, for the assessment of AREG levels. A dextran sulfate sodium (DSS)-induced chronic colitis model was established in wild type (WT) and <em>Areg</em>-knockout (<em>Areg^-/-</em>) mice. RNA-sequencing (RNA-seq) was performed on human intestinal fibroblasts (HIFs) to elucidate the underlying mechanisms. Additionally, the single-cell RNA-seq data of full-thickness CD, obtained from Prof. Rieder, was reanalyzed. Elevated levels of AREG were detected at stenotic sites in patients with CD. <em>Areg^-/-</em> colitis mice exhibited decreased intestinal fibrosis. AREG enhanced the activation and proliferation of HIFs by activating the PI3K/AKT pathway. The inhibitor of the PI3K/AKT pathway effectively suppressed AREG-induced activation and proliferation of HIFs and attenuated colitis-associated fibrosis in mice. In stricturing CD, inflammatory monocytes exhibited higher AREG levels, contributing to the activation and proliferation of intestinal fibroblasts. Adoptive transfer of <em>Ly6c</em>^hi inflammatory monocytes from WT but not <em>Areg</em>^-/- mice exacerbated intestinal fibrosis in DSS-induced colitis mice. These findings reveal that inflammatory monocytes derived-AREG promotes intestinal fibrosis in experimental colitis and CD patients by promoting intestinal fibroblasts activation and proliferation through the PI3K/AKT pathway. Inflammatory monocytes serve as the primary source of AREG in stricturing CD, critically mediating fibroblast-related fibrotic progression in an AREG-dependent manner. Therefore, AREG, the PI3K/AKT pathway and inflammatory monocytes may serve as potential therapeutic targets for intestinal fibrosis in CD.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 989-1000"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved humanized mouse model of Staphylococcus aureus infection","authors":"Hui Wang ,&nbsp;Dane Parker","doi":"10.1016/j.mucimm.2025.05.001","DOIUrl":"10.1016/j.mucimm.2025.05.001","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> is a significant cause of pulmonary infections, but existing mouse models fail to recapitulate human-specific responses. In this study, we developed a novel mouse model of <em>S. aureus</em> infection using humanized mice implanted with autologous fetal lung tissue. We show that these human lung implants support <em>S. aureus</em> survival and dissemination. Immunological profiling revealed extensive immune cell death after infection and an absence of chemokine induction. Transcriptomic profiling of the human lung implants revealed significant changes in gene expression, including NF-κB and JAK/STAT signaling. We identified upregulation of <em>Cyp24a1</em>, suggesting a role for vitamin D metabolism in host defense, but it had a mild effect on dissemination. Examination of the bacterial response to the host environment, found downregulation of virulence factors and metabolic genes, and upregulation of stress response pathways. The importance of the heat shock response in bacterial survival was shown as <em>hrcA</em>-deficient <em>S. aureus</em> exhibited reduced tissue colonization. These findings underscore the utility of this humanized lung model for studying <em>S. aureus</em> pathogenesis and bacterial adaptation to the human pulmonary environment.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 911-917"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distal airway epithelial progenitors mediate TGF-β release to drive lung CD8+ TRM induction following mucosal BCG vaccination","authors":"Judith A. Blake ,&nbsp;Julia Seifert ,&nbsp;Socorro Miranda-Hernandez ,&nbsp;Roland Ruscher ,&nbsp;Paul R. Giacomin ,&nbsp;Denise L. Doolan ,&nbsp;Andreas Kupz","doi":"10.1016/j.mucimm.2025.05.007","DOIUrl":"10.1016/j.mucimm.2025.05.007","url":null,"abstract":"<div><div>A principal reason for the high global morbidity and mortality of tuberculosis (TB) is the lack of efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG), as intradermal BCG does not induce local pulmonary immune memory. Animal studies have shown that inhalation of BCG vaccination provides superior mucosal protection against TB due to generation of lung resident memory T cells (T_RM). Here, we demonstrated that following mucosal vaccination with the genetically modified more virulent BCG strain, BCG::RD1, distal airway epithelial progenitors were mobilized to assist with restoration of alveolar epithelium. By way of their integrin-mediated activation of latent TGF-β, lung CD8⁺ T_RM differentiation was induced. Mucosal vaccinations using nonvirulent strains of BCG in which airway epithelial progenitors were not mobilized, as well as genetic inhibition of integrin-mediated activation of TGF-β, resulted in significantly lower numbers of lung CD8⁺ T_RM with subsequent reduced protection against <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>)<em>-</em>induced lung pathology in mice. The results link airway epithelial progenitor-mediated repair of injured lung tissue with a role in the induction of resident CD8⁺ T cell memory. These findings provide further explanation why mucosal vaccination with virulent BCG strains is more protective against TB and thus has implications for future TB vaccine development.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 4","pages":"Pages 973-988"},"PeriodicalIF":7.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lifelong partners: Gut microbiota-immune cell interactions from infancy to old age","authors":"Julia A. Brown ,&nbsp;Hilal Bashir ,&nbsp;Melody Y. Zeng","doi":"10.1016/j.mucimm.2025.01.006","DOIUrl":"10.1016/j.mucimm.2025.01.006","url":null,"abstract":"<div><div>Our immune system and gut microbiota are intricately coupled from birth, both going through maturation during early life and senescence during aging almost in a synchronized fashion. The symbiotic relationship between the human host and microbiota is critically dependent on a healthy immune system to keep our microbiota in check, while the microbiota provides essential functions to promote the development and fitness of our immune system. The partnership between our immune system and microbiota is particularly important during early life, when microbial ligands and metabolites shape the development of the immune cells and immune tolerance; during aging, having sufficient beneficial gut bacteria is critical for the maintenance of intact mucosal barriers, immune metabolic fitness, and strong immunity against pathogens. The immune system during childhood is programmed, with the support of the microbiota, to develop robust immune tolerance, and limit autoimmunity and metabolic dysregulation, which are prevalent during aging. This review comprehensively explores the mechanistic underpinnings of gut microbiota-immune cell interactions during infancy and old age, with the goal to gain a better understanding of potential strategies to leverage the gut microbiota to combat age-related immune decline.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 509-523"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronological maturation of the skin immune barrier is topographically different","authors":"Anikó Kapitány ,&nbsp;Lilla Soltész ,&nbsp;Vivien Stercel ,&nbsp;Lilla Szabó ,&nbsp;Orsolya Somogyi ,&nbsp;Eszter Anna Janka ,&nbsp;Viktória Nagy ,&nbsp;Szilárd Póliska ,&nbsp;Krisztián Gáspár ,&nbsp;Zoltán Hendrik ,&nbsp;Dániel Törőcsik ,&nbsp;Zsolt Dajnoki ,&nbsp;Andrea Szegedi","doi":"10.1016/j.mucimm.2025.03.004","DOIUrl":"10.1016/j.mucimm.2025.03.004","url":null,"abstract":"<div><div>Adult skin varies across regions, with differences in chemical, physical, microbiota, and immune barriers. However, data on topographical immune differences in other age groups are limited. This study aimed to explore the chronological maturation of the immune barrier in various skin regions.</div><div>A TaqMan low-density array and immunohistochemical and immunofluorescence detection of various immune cells and mediators in sebaceous gland-rich (SGR) and gland-poor (GP) healthy skin were performed in children, adolescents, and adults.</div><div>The maturation of SGR skin showed a general upward trend in the mRNA levels of most Th17-related molecules with a significant increase in IL-1B from childhood to adulthood, but with only a slight elevation between childhood and adolescence. In addition, T cell, Treg, dendritic cell (DC) counts, as well as the levels of several Th17-related proteins (IL-17, IL-10, IL-23, CCL20, S100A8, sfTSLP, LCN2), increased significantly with age. In GP skin, AHR mRNA levels decreased, while Th17-related protein levels increased, although only moderately. When comparing the two regions, SGR and GP skin were similar in childhood, with differences emerging in adolescence and becoming significant in adulthood, particularly in the IL-17 pathway, mainly produced by Th17 cells.</div><div>Our results show a similarly directed maturation process in GP and SGR regions, with more pronounced development of the SGR skin immune barrier (with more immune cell infiltration and cytokine production) during and after the adolescence. This is likely to be related to the significant changes in the chemical and microbiota barriers of the SGR skin during adolescence, and may explain the high incidence of inflammatory skin diseases on the SGR skin of adolescents, highlighting the need for targeted skin care in this region.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 730-741"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung-resident memory Th2 cells regulate pulmonary cryptococcosis by inducing type-II granuloma formation","authors":"Keigo Ueno ,&nbsp;Akiko Nagamori ,&nbsp;Nahoko Oniyama Honkyu ,&nbsp;Kyung J. Kwon-Chung ,&nbsp;Yoshitsugu Miyazaki","doi":"10.1016/j.mucimm.2025.02.004","DOIUrl":"10.1016/j.mucimm.2025.02.004","url":null,"abstract":"<div><div>Lung-resident memory T cells (lung TRMs) settle in the lung and respond rapidly to external antigens, and are therefore considered to have great potential for development of respiratory vaccines. Here, we demonstrate that lung-resident memory Th2 cells (lung TRM2) protect against pulmonary mycosis caused by <em>Cryptococcus gattii</em>. We developed novel whole-cell intranasal vaccines using a heat-inactivated <em>C.<!--> <!-->gattii</em> capsule-deficient strain <em>cap59</em>Δ, which induced ST-2⁺ Gata-3⁺ lung TRM2 specifically responding to <em>C.<!--> <!-->gattii</em> whole-cell antigen. Lung fungal burden and survival rate were significantly improved in immunized mice after infection challenge. The immunosuppressive agent FTY720 did not impact vaccine effectiveness, and adoptive transfer of lung TRMs into Rag-1-deficient mice decreased the lung fungal burden. In IL-4/IL-13 double-knockout (DKO) mice, immunization did not efficiently induce eosinophil recruitment and granuloma formation, and the fungal burden was not decreased after infection challenge. Co-culture of lung TRM2 with myeloid lineages induced multinucleated giant cells (MGCs) in the presence of antigen, which phagocytosed live <em>C.<!--> <!-->gattii</em> cells without opsonization, whereas lung TRM2 from DKO mice did not induce MGCs. These findings provide a new model in which lung TRM2 suppress <em>C.<!--> <!-->gattii</em> infection via granuloma induction.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 631-642"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472230","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}