Mucosal Immunology最新文献

{"title":"Increased ocular plasma cells induce damaging α-synuclein+ microglia in autoimmune uveitis","authors":"Minghao Li ,&nbsp;Meng Feng ,&nbsp;Tingting Liu ,&nbsp;Songqi Duan ,&nbsp;Xuejing Man ,&nbsp;Xiaomeng Yuan ,&nbsp;Lijie Wang ,&nbsp;Yu Sun ,&nbsp;Xunbin Wei ,&nbsp;Qiang Fu ,&nbsp;Baofa Sun ,&nbsp;Wei Lin","doi":"10.1016/j.mucimm.2025.02.007","DOIUrl":"10.1016/j.mucimm.2025.02.007","url":null,"abstract":"<div><div>Autoimmune uveitis (AIU) is an immune-inflammatory disease that can lead to blindness. However, incomplete understanding of the involved immune cell subsets and their contributions to retinal injury has hindered the development of effective AIU therapies. Using single-cell RNA sequencing and immunofluorescence, we identified α-synuclein⁺ microglia as the primary subset of damaged ocular cells in the eyes of the experimental autoimmune uveitis (EAU) mouse model. Ocular-infiltrating plasma cells (PCs) were shown to express multiple inflammatory factors, particularly TNF-α, which promoted the production of α-synuclein⁺ microglia. Studies of heterogeneous PC subtypes revealed that MUC1^- PCs represent the primary pathogenic subset, secreting multiple cytokines. Although MUC1⁺ PCs expressed TGF-β, they exhibited long-lived characteristics and secreted IgG and IgM, thereby prolonging disease progression. Finally, the small G protein Rab1A, also expressed in the PCs of Vogt-Koyanagi-Harada (VKH) patients, was found to mediate autophagy and NF-κB expression, influencing PCs survival and inflammatory responses. Silencing or knocking down Rab1A in PCs inhibited their survival. This study elucidates potential mechanisms underlying the neuroimmune inflammatory response and highlights the previously unrecognized role of infiltrating PCs in AIU, offering novel therapeutic targets for this disease.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 668-684"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523990","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":"Intrapulmonary-administered myeloid derived suppressor cells rescue mice from Pseudomonas aeruginosa infection and promote a regulatory/repair phenotype","authors":"Maëlys Born-Bony ,&nbsp;Clémentine Cornu ,&nbsp;Bérengère Villeret ,&nbsp;Valérie Gratio ,&nbsp;Romé Voulhoux ,&nbsp;Jean-Michel Sallenave","doi":"10.1016/j.mucimm.2025.03.001","DOIUrl":"10.1016/j.mucimm.2025.03.001","url":null,"abstract":"<div><div>Pseudomonas aeruginosa (P.aeruginosa) is a pathogenic opportunistic bacterium, classified as a priority by the WHO for the research of new treatments. As this bacterium is harmful through the inflammation and tissue damage it causes, we investigated the role of Myeloid Derived Suppressor Cells (MDSC) in P.aeruginosa infections and their potential as a therapeutic tool. Using both ‘classically’ obtained MDSC (through mice bone-marrow differentiation), and a new procedure developed here (using the ER-Hoxb8 hematopoietic cell line), we observed that after administering intra-nasally a lethal dose of P.aeruginosa (PAO1), intra-pulmonary transfer of MDSC, in both prophylactic and therapeutic protocols, markedly improves survival of <em>P.aeruginosa</em> infected animals. Mechanistically, with a sub-lethal dose of <em>P.aeruginosa</em>, we observed that MDSC transfer modulated lung tissue injury, down-regulated inflammatory responses and elicited lung repair. We further showed that WT-PAO1 and MDSC (and their subtypes PMN-MDSC and M−MDSC) could interact directly <em>in vitro</em> and <em>in vivo</em>, and that both PMN- and M−MDSC gene expression (assessed through RNA sequencing) was modulated after <em>in vitro P.aeruginosa</em> infection, and that WT-PAO1 (but not ΔFlic-PAO1) infection led to inhibition of T cell proliferation and promoted epithelial cell wound healing. Furthermore, we showed that the transcription factor Nr4A1 was up-regulated in both PMN- and M−MDSC- infected cells and may be an important mediator in the process. Altogether, we highlight a potential beneficial role of MDSC in P.aeruginosa infection responses and suggest that the unique properties of these cells make them attractive potential new therapeutic tools for patients with acute or chronic inflammatory diseases.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 700-716"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663925","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":"Microbial remodeling of gut tryptophan metabolism and indole-3-lactate production regulate epithelial barrier repair and viral suppression in human and simian immunodeficiency virus infections","authors":"Clarissa Santos Rocha ,&nbsp;Katie L. Alexander ,&nbsp;Carolina Herrera ,&nbsp;Mariana G. Weber ,&nbsp;Irina Grishina ,&nbsp;Lauren A. Hirao ,&nbsp;Dylan J. Kramer ,&nbsp;Juan Arredondo ,&nbsp;Abigail Mende ,&nbsp;Katti R. Crakes ,&nbsp;Anne N. Fenton ,&nbsp;Maria L. Marco ,&nbsp;David A. Mills ,&nbsp;John C. Kappes ,&nbsp;Lesley E. Smythies ,&nbsp;Paul Ziprin ,&nbsp;Sumathi Sankaran-Walters ,&nbsp;Phillip D. Smith ,&nbsp;Satya Dandekar","doi":"10.1016/j.mucimm.2025.01.011","DOIUrl":"10.1016/j.mucimm.2025.01.011","url":null,"abstract":"<div><div>Gut inflammatory diseases cause microbial dysbiosis. Human immunodeficiency virus-1 (HIV) infection disrupts intestinal integrity, subverts repair/renewal pathways, impairs mucosal immunity and propels microbial dysbiosis. However, microbial metabolic mechanisms driving repair mechanisms in virally inflamed gut are not well understood. We investigated the capability and mechanisms of gut microbes to restore epithelial barriers and mucosal immunity in virally inflamed gut by using a multipronged approach: an <em>in vivo</em> simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, <em>ex vivo</em> HIV-exposed human colorectal explants and primary human intestinal epithelial cells. SIV infection reprogrammed tryptophan (TRP) metabolism, increasing kynurenine catabolite levels that are associated with mucosal barrier disruption and immune suppression. Administration of <em>Lactiplantibacillus plantarum</em> or <em>Bifidobacterium longum</em> subsp<em>. infantis</em> into the SIV-inflamed gut lumen <em>in vivo</em> resulted in rapid reprogramming of microbial TRP metabolism towards indole-3-lactic acid (ILA) production. This shift accelerated epithelial repair and enhanced anti-viral defenses through induction of IL-22 signaling in mucosal T cells and aryl hydrocarbon receptor activation. Additionally, ILA treatment of human colorectal tissue explants <em>ex vivo</em> inhibited HIV replication by reducing mucosal inflammatory cytokine production and cell activation. Our findings underscore the therapeutic potential of microbial metabolic reprogramming of TRP-to-ILA and mechanisms in mitigating viral pathogenic effects and bolstering mucosal defenses for HIV eradication.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 583-595"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080673","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":"Damage sensing through TLR9 regulates inflammatory and antiviral responses during influenza infection","authors":"Jooyoung Kim ,&nbsp;Yifan Yuan ,&nbsp;Karen Agaronyan ,&nbsp;Amy Zhao ,&nbsp;Victoria D Wang ,&nbsp;David Gau ,&nbsp;Nicholas Toosi ,&nbsp;Gayatri Gupta ,&nbsp;Heran Essayas ,&nbsp;Ayelet Kaminski ,&nbsp;John McGovern ,&nbsp;Sheeline Yu ,&nbsp;Samuel Woo ,&nbsp;Chris J. Lee ,&nbsp;Shifa Gandhi ,&nbsp;Tina Saber ,&nbsp;Tayebeh Saleh ,&nbsp;Buqu Hu ,&nbsp;Ying Sun ,&nbsp;Genta Ishikawa ,&nbsp;Lokesh Sharma","doi":"10.1016/j.mucimm.2025.01.008","DOIUrl":"10.1016/j.mucimm.2025.01.008","url":null,"abstract":"<div><div>Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA (mtDNA), which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mtDNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data showed that TLR9-mediated sensing of tissue damage promoted an inflammatory response during early infection, driven by epithelial and myeloid cells. Along with the diminished inflammatory response, the absence of TLR9 led to impaired viral clearance manifested as higher and prolonged influenza components in myeloid cells, including monocytes and macrophages, rendering them highly inflammatory. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we found elevated TLR9 ligands in the plasma samples of patients with influenza infection and its association with the disease severity in hospitalized patients, demonstrating its clinical relevance. Overall, we demonstrated an essential role of damage sensing through TLR9 in promoting anti-influenza immunity and inflammatory response.</div></div><div><h3>Author Summary</h3><div>Tissue damage is an inevitable outcome of clinically relevant lung infections, but the host mechanisms for detecting such damage during infection are not well understood. We investigated the role of Toll-like receptor 9 (TLR9) in sensing tissue damage caused by influenza. Since influenza lacks TLR9 ligands, we hypothesized that TLR9 signaling is driven by tissue damage molecules like mitochondrial DNA (mtDNA). Our data revealed that TLR9 deficiency reduces early inflammatory lung injury but impairs viral clearance, resulting in extensive infection of immune cells, persistent inflammation, and delayed recovery. Myeloid-specific TLR9 deletion ameliorated late-stage inflammatory responses. In humans, influenza-infected individuals exhibited elevated TLR9 activity and mtDNA levels in plasma compared to healthy controls, with higher TLR9 activation potential correlating with severe disease requiring ICU admission. These findings suggest that TLR9-mediated damage sensing triggers both inflammatory tissue injury and viral clearance. These data indicate that TLR9 activity can serve as a crucial biomarker and therapeutic target to limit influenza-induced tissue injury.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 537-548"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066829","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":"IL-6 mediates defense against influenza virus by promoting protective antibody responses but not innate inflammation","authors":"F. Piattini,&nbsp;N.D. Sidiropoulos,&nbsp;I. Berest,&nbsp;M. Kopf","doi":"10.1016/j.mucimm.2025.02.001","DOIUrl":"10.1016/j.mucimm.2025.02.001","url":null,"abstract":"<div><div>Influenza virus infection is a leading cause of morbidity and mortality worldwide, posing a significant public health problem. The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown to promote defense against respiratory viral infection, while excessive IL-6 responses have been associated with severe pneumonia. Heterogenous expression of IL-6R and the IL-6-signal transducer subunit (gp130) across many cell types and different signaling modalities have made it difficult to define the precise role of the IL-6/IL-6R pathway <em>in vivo</em>. We generated multiple cell lineage-specific <em>Il6ra</em>-deficient mice and compared them to global <em>Il6ra^-/-</em> and <em>Il-6^-/-</em> mice to dissect the systemic and cell-intrinsic mechanisms for pneumonitis and control of influenza A virus (IAV) infection. Delayed viral clearance and severe morbidity in the global IL-6 knockouts were associated with reduced antibody responses, complement C3 and C5 production, and impaired T follicular helper (Tfh) cell generation. Mice lacking IL-6R exclusively in T cells phenocopied a defect in Tfh cell differentiation and antibody production, although susceptibility to IAV was only mildly affected. Mice lacking IL-6R specifically in B cells mounted normal antibody responses. Moreover, innate pro-inflammatory cytokine responses, myeloid cell infiltration, and adaptive immunity in the lung remained unaffected in <em>Il6ra</em>^fl/fl<em>LysM^Cr</em>^e mice. Our results suggest that IL-6 mediates defense against IAV mainly by generating Tfh cells and promoting local C3 production, which together are required for eliciting protective antibody responses by B cells.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 596-606"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468598","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":"Single-cell sequencing reveals the same heterogeneity of neutrophils in heatstroke-induced lung and liver injury","authors":"Fuquan Wang ,&nbsp;Yan Zhang ,&nbsp;Miaomiao Sun ,&nbsp;Mengyu Li ,&nbsp;Yu Wang ,&nbsp;Dingyu Zhang ,&nbsp;Shanglong Yao","doi":"10.1016/j.mucimm.2025.03.005","DOIUrl":"10.1016/j.mucimm.2025.03.005","url":null,"abstract":"<div><div>Heatstroke (HS) is typically considered a sepsis-like syndrome caused by hyperthermia, often accompanied by multiple organ dysfunctions (MODS). To explore the mechanisms of MODS, we established a mouse model of HS by exposing mice to a hyperthermic and high-humidity environment. Then, we utilized single-cell RNA sequencing (scRNA-seq) to depict the cellular landscape of HS mice lung tissue and liver tissue. We found that the enhancement of neutrophil infiltration mediated by the “Cxcr2-Cxcl2″ receptor-ligand pair is a prominent feature of HS-induced lung injury. By effectively suppressing the recruitment of neutrophils in HS-induced lung injury, the application of Cxcr2 inhibitor held positive implications for improving HS-induced lung injury. In addition to the chemotactic effect of immune cells on neutrophils, we identified a subcluster of fibroblasts labeled as Col14a1+, which possessed notable chemotactic factor-secretion characteristics and likely exerted a role in the early stages of neutrophil infiltration. Furthermore, our study unveiled significant heterogeneity among neutrophils within the HS-induced lung injury. Particularly, Cd177 + neutrophils exhibited a dominant presence, characterized by heightened pro-inflammatory responses and oxidative stress. In heatstroke-induced liver injury, neutrophils exhibited similar heterogeneous characteristics. Cd177 + neutrophils exhibited an enhanced ability to produce neutrophil extracellular traps (NETs) while lowering the levels of NETs can significantly improve heatstroke-induced lung and liver injury. Additionally, our study identified Cebpe as a key transcriptional regulatory factor in Cd177 + neutrophil differentiation. Knockdown of the expression of Cebpe can suppress the Cd177 + neutrophil differentiation and decrease the expression levels of NETs. Our research indicated a common heterogeneity in neutrophils during MODS in HS. Cd177 + neutrophils contributed to organ damage in HS, and Cebpe may serve as a crucial intervention target in the treatment of HS.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 3","pages":"Pages 742-756"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753512","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⁺ T_RM induction following mucosal BCG vaccination.","authors":"Judith A Blake, Julia Seifert, Socorro Miranda-Hernandez, Roland Ruscher, Paul R Giacomin, Denise L Doolan, Andreas Kupz","doi":"10.1016/j.mucimm.2025.05.007","DOIUrl":"10.1016/j.mucimm.2025.05.007","url":null,"abstract":"<p><p>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 Mycobacterium tuberculosis (Mtb)-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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-30","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":"MAIT cells exacerbate colonic inflammation in a genetically diverse murine model of spontaneous colitis.","authors":"Liyen Loh, David J Orlicky, Andrea Spengler, Joanne Domenico, Jared Klarquist, Cassandra Levens, Sofia Celli, Jennifer M Kofonow, Charles E Robertson, Olivier Lantz, Francois Legoux, Daniel N Frank, Jennifer Matsuda, Paul J Norman, Kristine A Kuhn, Joseph Onyiah, Laurent Gapin","doi":"10.1016/j.mucimm.2025.05.006","DOIUrl":"10.1016/j.mucimm.2025.05.006","url":null,"abstract":"<p><p>IL-17-producing lymphocytes are involved in both tissue repair and the propagation of inflammation, with their effects highly context-dependent. Mucosal-Associated-Invariant-T-cells (MAIT), a subset of innate-like T cells with features of both Th1 and Th17 lineages, are increasingly recognized for their roles in mucosal immunity. Here, we identified the Collaborative-Cross CC011/Unc strain, which spontaneously develops chronic colitis, as being enriched for MAIT cells. This expansion coincides with an age-related loss of intestinal barrier permeability and colonic inflammation. Microbiota from CC011 mice activated MAIT cells in an MR1-dependent manner and selectively promoted the accumulation of MAIT17 cells in peripheral tissues. Single-cell transcriptomic analyses revealed colon MAIT cells from colitic CC011 mice expressed a pathogenic Th17-like signature, characterized by IL-1 and IL-23 signaling, IL-17A and IFNγ co-expression, and upregulation of IL-23R, features that correlated with inflammatory Ly6C^hi monocyte abundance. Genetic deletion of Traj33, essential for MAIT development, significantly reduced colonic inflammation in this model. These findings demonstrate that MAIT cells integrate microbial and cytokine cues to adopt a pathogenic effector phenotype that exacerbates chronic intestinal inflammation.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory chemokine receptors CCR1, CCR2, CCR3 and CCR5 are essential for an optimal T cell response to influenza.","authors":"Marieke Pingen, Catherine E Hughes, Laura Medina-Ruiz, Heather Mathie, Jennifer A Barrie, Chris Ah Hansell, Robin Bartolini, Megan Kl MacLeod, Gerard J Graham","doi":"10.1016/j.mucimm.2025.05.005","DOIUrl":"10.1016/j.mucimm.2025.05.005","url":null,"abstract":"<p><p>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. 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. 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. 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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-23","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":"Inducible, but not constitutive, pancreatic REG/Reg isoforms are regulated by intestinal microbiota and pancreatic diseases.","authors":"Yixuan D Zhou, Macy R Komnick, Fabiola Sepulveda, Grace Liu, Elida Nieves-Ortiz, Kelsey Meador, Ornella Ndatabaye, Aliia Fatkhullina, Asha Bozicevich, Braden Juengel, Natalie J Wu-Woods, Paulina M Naydenkov, Johnathan Kent, Nathaniel Christiansen, Maria Lucia Madariaga, Piotr Witkowski, Rustem F Ismagilov, Daria Esterházy","doi":"10.1016/j.mucimm.2025.05.003","DOIUrl":"10.1016/j.mucimm.2025.05.003","url":null,"abstract":"<p><p>The REG/Reg gene locus encodes a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in humans and mice, the pancreas and gut differed in REG/Reg isoform levels and preferences, with the duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as \"inducible\" and others as \"constitutive\". Indeed, in pancreatic ductal adenocarcinoma and pancreatitis models, only inducible Reg members were upregulated in the pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG/Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}