Mucosal Immunology最新文献

{"title":"Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen","authors":"Gesa J. Albers ,&nbsp;Christina Michalaki ,&nbsp;Patricia P. Ogger ,&nbsp;Amy F. Lloyd ,&nbsp;Benjamin Causton ,&nbsp;Simone A. Walker ,&nbsp;Anna Caldwell ,&nbsp;John M. Halket ,&nbsp;Linda V. Sinclair ,&nbsp;Sarah H. Forde ,&nbsp;Cormac McCarthy ,&nbsp;Timothy S.C. Hinks ,&nbsp;Clare M. Lloyd ,&nbsp;Adam J. Byrne","doi":"10.1016/j.mucimm.2024.10.002","DOIUrl":"10.1016/j.mucimm.2024.10.002","url":null,"abstract":"<div><div>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 <em>in vivo</em>, 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 <em>in vivo</em>. 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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 121-134"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470338","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}

{"title":"Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function","authors":"Nai-Wen Fan ,&nbsp;Man Yu ,&nbsp;Shudan Wang ,&nbsp;Tomas Blanco ,&nbsp;Zala Luznik ,&nbsp;Sunil K. Chauhan ,&nbsp;Veena Viswanath ,&nbsp;Daniel Gil ,&nbsp;Katherine Held ,&nbsp;Yihe Chen ,&nbsp;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⁺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.<em>Rag1^-/-</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}

{"title":"Herpes stromal keratitis erodes the establishment of tissue-resident memory T cell pool in HSV-1 infected corneas","authors":"Mizumi Setia ,&nbsp;Pratima Krishna Suvas ,&nbsp;Mashidur Rana ,&nbsp;Anish Chakraborty ,&nbsp;Susmit Suvas","doi":"10.1016/j.mucimm.2024.11.003","DOIUrl":"10.1016/j.mucimm.2024.11.003","url":null,"abstract":"<div><div>The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (T_RM) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of T_RM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 T_RM cells than HSK corneas. The T_RM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of T_RM cells in HSV-1 infected corneas that did or did not develop HSK.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 188-204"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710602","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}

{"title":"The C-type lectin receptor MINCLE interferes with eosinophil function and protective intestinal immunity in Strongyloides ratti-infected mice","authors":"Lara Linnemann ,&nbsp;Jennifer Antwi-Ekwuruke ,&nbsp;Vinayaga Gnanapragassam ,&nbsp;Corinna Bang ,&nbsp;Malte Rühlemann ,&nbsp;Jürgen Ruland ,&nbsp;Wiebke Hartmann ,&nbsp;Lennart Heepmann ,&nbsp;Sara Dörken ,&nbsp;Saleh M. Yunus ,&nbsp;Birte Viebrock ,&nbsp;Annette Schlosser ,&nbsp;Bernd Lepenies ,&nbsp;Minka Breloer","doi":"10.1016/j.mucimm.2024.11.005","DOIUrl":"10.1016/j.mucimm.2024.11.005","url":null,"abstract":"<div><div><em>Strongyloides ratti</em> is a helminth parasite that displays tissue-migrating and intestinal life stages. Myeloid C-type lectin receptors (CLRs) are pattern recognition receptors that recognize pathogen-derived ligands and initiate immune responses. To date, the role of CLRs in <em>S. ratti</em> infection has not been investigated. Here, we show that <em>S. ratti</em>-derived ligands are recognized by the CLR Macrophage inducible Ca²⁺-dependent lectin receptor (MINCLE). While MINCLE-deficiency did not affect initiation of a protective anti-<em>S. ratti</em> type 2 immunity, MINCLE-deficient mice had a transient advantage in intestinal immunity. Unravelling the underlying mechanism, we show that next to macrophages, dendritic cells and neutrophils, a fraction of eosinophils express MINCLE and expand during <em>S. ratti</em> infection. MINCLE-deficient eosinophils exhibited a more active phenotype and prolonged expansion <em>in vivo</em> and displayed increased capacity to reduce <em>S. ratti</em> motility and produce reactive oxygen species <em>in vitro</em>, compared to wild-type (WT) eosinophils. Depletion of eosinophils in <em>S. ratti</em>-infected mice after the tissue-migration phase elevated intestinal worm burden in MINCLE-deficient mice to the WT level. Thus, our findings establish a central contribution of eosinophils to parasite ejection from the intestine and suggest that <em>S. ratti</em>-triggered signalling via MINCLE interferes with eosinophil mediated ejection of <em>S. ratti</em> from the intestine.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 220-231"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710607","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}

{"title":"Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes","authors":"Maud Heredia ,&nbsp;Mohammed Charrout ,&nbsp;Renz C.W. Klomberg ,&nbsp;Martine A. Aardoom ,&nbsp;Maria M.E. Jongsma ,&nbsp;Polychronis Kemos ,&nbsp;Danielle H. Hulleman-van Haaften ,&nbsp;Bastiaan Tuk ,&nbsp;Lisette A. van Berkel ,&nbsp;Brenda Bley Folly ,&nbsp;Beatriz Calado ,&nbsp;Sandrine Nugteren ,&nbsp;Ytje Simons-Oosterhuis ,&nbsp;Michail Doukas ,&nbsp;Mathijs A. Sanders ,&nbsp;Gregory van Beek ,&nbsp;Frank M. Ruemmele ,&nbsp;Nicholas M. Croft ,&nbsp;Ahmed Mahfouz ,&nbsp;Marcel J.T. Reinders ,&nbsp;Janneke N. Samsom","doi":"10.1016/j.mucimm.2024.09.004","DOIUrl":"10.1016/j.mucimm.2024.09.004","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn’s disease, CD: <em>n</em> = 62; ulcerative colitis, UC: <em>n</em> = 20; age-matched controls <em>n</em> = 43), and after 10–12 weeks’ induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 76-89"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350418","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}

{"title":"How the early life microbiome shapes immune programming in childhood asthma and allergies","authors":"Courtney Hoskinson,&nbsp;Charisse Petersen,&nbsp;Stuart E. Turvey","doi":"10.1016/j.mucimm.2024.12.005","DOIUrl":"10.1016/j.mucimm.2024.12.005","url":null,"abstract":"<div><div>Despite advances in our understanding of their diagnosis and treatment, pediatric allergies impose substantial burdens on affected children, families, and healthcare systems. Further, the prevalence of allergic diseases has dramatically increased over the past half-century, leading to additional concerns and concerted efforts to identify the origins, potential predictors and preventions, and therapies of allergic diseases. Together with the increase in allergic diseases, changes in lifestyle and early-life environmental influences have corresponded with changes in colonization patterns of the infant gut microbiome. The gut microbiome plays a key role in developing the immune system, thus greatly influencing the development of allergic disease. In this review, we specifically highlight the importance of the proper maturation and composition of the gut microbiome as an essential step in healthy child development or disease progression. By exploring the intertwined development of the immune system and microbiome across pediatric allergic diseases, we provide insights into potential novel strategies for their prevention and management.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 26-35"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829353","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}

{"title":"Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells","authors":"Maik Luu ,&nbsp;Felix F Krause ,&nbsp;Heide Monning ,&nbsp;Anne Wempe ,&nbsp;Hanna Leister ,&nbsp;Lisa Mainieri ,&nbsp;Sarah Staudt ,&nbsp;Kai Ziegler-Martin ,&nbsp;Kira Mangold ,&nbsp;Nora Kappelhoff ,&nbsp;Yoav D Shaul ,&nbsp;Stephan Göttig ,&nbsp;Carlos Plaza-Sirvent ,&nbsp;Leon N Schulte ,&nbsp;Isabelle Bekeredjian-Ding ,&nbsp;Ingo Schmitz ,&nbsp;Ulrich Steinhoff ,&nbsp;Alexander Visekruna","doi":"10.1016/j.mucimm.2024.09.003","DOIUrl":"10.1016/j.mucimm.2024.09.003","url":null,"abstract":"<div><div>The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκB_NS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal <em>Clostridium sporogenes</em>, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 66-75"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254726","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}

{"title":"Dietary influence and immune balance: Regulating CD4+ IEL responses and MHCII in the gut","authors":"Jan Dobeš ,&nbsp;Tomáš Brabec","doi":"10.1016/j.mucimm.2024.12.011","DOIUrl":"10.1016/j.mucimm.2024.12.011","url":null,"abstract":"","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 36-38"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872586","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}

{"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, Katie L Alexander, Carolina Herrera, Mariana G Weber, Irina Grishina, Lauren A Hirao, Dylan J Kramer, Juan Arredondo, Abigail Mende, Katti R Crakes, Anne N Fenton, Maria L Marco, David A Mills, John C Kappes, Lesley E Smythies, Paul Ziprin, Sumathi Sankaran-Walters, Phillip D Smith, Satya Dandekar","doi":"10.1016/j.mucimm.2025.01.011","DOIUrl":"10.1016/j.mucimm.2025.01.011","url":null,"abstract":"<p><p>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 in vivo simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, ex vivo 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 Lactiplantibacillus plantarum or Bifidobacterium longum subsp. infantis into the SIV-inflamed gut lumen in vivo 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 ex vivo 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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-31","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, Yifan Yuan, Karen Agaronyan, Amy Zhao, Victoria D Wang, David Gau, Nicholas Toosi, Gayatri Gupta, Heran Essayas, Ayelet Kaminski, John McGovern, Sheeline Yu, Samuel Woo, Chris J Lee, Shifa Gandhi, Tina Saber, Tayebeh Saleh, Buqu Hu, Ying Sun, Genta Ishikawa, William Bain, John Evankovich, Lujia Chen, HongDuck Yun, Erica L Herzog, Charles S Dela Cruz, Changwan Ryu, Lokesh Sharma","doi":"10.1016/j.mucimm.2025.01.008","DOIUrl":"10.1016/j.mucimm.2025.01.008","url":null,"abstract":"<p><p>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. AUTHOR SUMMARY: 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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-28","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}