Pub Date : 2025-10-14DOI: 10.1038/s41423-025-01356-w
Yuan Tang, Yue Zhao, Zixiang Chen, Xiaofei Shi, Yingbo Zhou, Lingqin Li, Fan Xiao, Xiaoxia Zhu, Yufeng Qing, Yingqian Mo, Xiaoping Hong, Dongzhou Liu, Ke Rui, Jie Tian, Liwei Lu
Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage, but the role of interleukin-18 (IL-18), a cytokine associated with inflammasome activation, in modulating the T-cell response and autoimmune pathogenesis remains largely unclear. In this study, we detected high expression levels of the IL-18 receptor α chain (IL-18Rα) in murine and human Th17 cells. In culture, IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production, a phenotype of pathogenic Th17 (pTh17) cells. Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures. Mechanistically, IL-18 promoted Stat3 phosphorylation, which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production. In patients with primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE), IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity. Moreover, the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren’s syndrome (ESS) model mice and the renal tissues of lupus model mice. Furthermore, adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice, whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice. Together, our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development, indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.
{"title":"IL-18 drives the Bhlhe40-mediated pathogenic Th17 cell response and exacerbates autoimmune disease progression","authors":"Yuan Tang, Yue Zhao, Zixiang Chen, Xiaofei Shi, Yingbo Zhou, Lingqin Li, Fan Xiao, Xiaoxia Zhu, Yufeng Qing, Yingqian Mo, Xiaoping Hong, Dongzhou Liu, Ke Rui, Jie Tian, Liwei Lu","doi":"10.1038/s41423-025-01356-w","DOIUrl":"10.1038/s41423-025-01356-w","url":null,"abstract":"Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage, but the role of interleukin-18 (IL-18), a cytokine associated with inflammasome activation, in modulating the T-cell response and autoimmune pathogenesis remains largely unclear. In this study, we detected high expression levels of the IL-18 receptor α chain (IL-18Rα) in murine and human Th17 cells. In culture, IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production, a phenotype of pathogenic Th17 (pTh17) cells. Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures. Mechanistically, IL-18 promoted Stat3 phosphorylation, which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production. In patients with primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE), IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity. Moreover, the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren’s syndrome (ESS) model mice and the renal tissues of lupus model mice. Furthermore, adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice, whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice. Together, our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development, indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1581-1597"},"PeriodicalIF":19.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1038/s41423-025-01348-w
Zhishan Zhao, Peng Wu, Qingman Li, Di Sun, Lize Wu, Yiping Xu, Fan Zhao, Dandan Wu, Ziwei Chen, Pengkun Yuan, Kaixiang Zhu, Xuexiao Jin, Pengfei Wang, Chenyi An, Dante Neculai, Wei Chen, Meiping Lu, Linrong Lu
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in maintaining peripheral immune tolerance, but its mechanisms of action are highly complicated. Here, through the generation of a gene knock-in (KI) mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation, we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions. Interestingly, although both KO and KI Treg cells lost the ability to endocytose B7 molecules, the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals. Therefore, this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4. Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease, providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.
{"title":"Dissection of the trans-endocytosis and signal inhibition functions of CTLA-4 through the study of a disease-associated Y139C mutation","authors":"Zhishan Zhao, Peng Wu, Qingman Li, Di Sun, Lize Wu, Yiping Xu, Fan Zhao, Dandan Wu, Ziwei Chen, Pengkun Yuan, Kaixiang Zhu, Xuexiao Jin, Pengfei Wang, Chenyi An, Dante Neculai, Wei Chen, Meiping Lu, Linrong Lu","doi":"10.1038/s41423-025-01348-w","DOIUrl":"10.1038/s41423-025-01348-w","url":null,"abstract":"Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in maintaining peripheral immune tolerance, but its mechanisms of action are highly complicated. Here, through the generation of a gene knock-in (KI) mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation, we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions. Interestingly, although both KO and KI Treg cells lost the ability to endocytose B7 molecules, the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals. Therefore, this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4. Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease, providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1506-1518"},"PeriodicalIF":19.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1038/s41423-025-01354-y
Sagar R. Dubey, Cynthia Turnbull, Abhimanu Pandey, Anyang Zhao, Melan Kurera, Radhwan Al-Zidan, Cheng Shen, Manjul Gautam, Shreya Mahajan, Poonam S. Jadhav, Aritra Ghosh, Chinh Ngo, Si Ming Man
The inflammasome is an inflammatory signaling protein complex comprising a sensor protein, the adaptor protein ASC, and the cysteine protease caspase-1. Inflammasome sensor proteins are activated by microbial molecular patterns, endogenous self-derived damage signals, or exogenous environmental danger signals. Multiple inflammasomes that differ in their mechanisms of action and structural composition have been identified. The best characterized are the canonical NLRP1, NLRP3, NAIP-NLRC4, AIM2, and Pyrin inflammasomes and the noncanonical inflammasomes activated by caspase-4, caspase-5 or caspase-11. The lesser known inflammasomes are the NLRP6, NLRP7, NLRP9, NLRP10, NLRP12, CARD8, and MxA inflammasomes. Following inflammasome assembly, caspase-1 promotes the secretion of the proinflammatory cytokines IL-1β and IL-18, and pyroptosis is mediated by the membrane-disrupting proteins gasdermin D and ninjurin-1. These functional activities control innate and adaptive immune responses and the initiation, development, and progression of autoinflammation, cancer, infectious diseases, and neurodegenerative diseases. Understanding how inflammasomes respond to pathogens and sterile signals has refined our view of innate immunity and offered new therapeutic targets. In this review, we present a comprehensive overview of inflammasomes with an emphasis on the mechanistic principles that govern inflammasome formation. We also discuss the contributions of inflammasome activation to health and disease.
{"title":"Molecular mechanisms and regulation of inflammasome activation and signaling: sensing of pathogens and damage molecular patterns","authors":"Sagar R. Dubey, Cynthia Turnbull, Abhimanu Pandey, Anyang Zhao, Melan Kurera, Radhwan Al-Zidan, Cheng Shen, Manjul Gautam, Shreya Mahajan, Poonam S. Jadhav, Aritra Ghosh, Chinh Ngo, Si Ming Man","doi":"10.1038/s41423-025-01354-y","DOIUrl":"10.1038/s41423-025-01354-y","url":null,"abstract":"The inflammasome is an inflammatory signaling protein complex comprising a sensor protein, the adaptor protein ASC, and the cysteine protease caspase-1. Inflammasome sensor proteins are activated by microbial molecular patterns, endogenous self-derived damage signals, or exogenous environmental danger signals. Multiple inflammasomes that differ in their mechanisms of action and structural composition have been identified. The best characterized are the canonical NLRP1, NLRP3, NAIP-NLRC4, AIM2, and Pyrin inflammasomes and the noncanonical inflammasomes activated by caspase-4, caspase-5 or caspase-11. The lesser known inflammasomes are the NLRP6, NLRP7, NLRP9, NLRP10, NLRP12, CARD8, and MxA inflammasomes. Following inflammasome assembly, caspase-1 promotes the secretion of the proinflammatory cytokines IL-1β and IL-18, and pyroptosis is mediated by the membrane-disrupting proteins gasdermin D and ninjurin-1. These functional activities control innate and adaptive immune responses and the initiation, development, and progression of autoinflammation, cancer, infectious diseases, and neurodegenerative diseases. Understanding how inflammasomes respond to pathogens and sterile signals has refined our view of innate immunity and offered new therapeutic targets. In this review, we present a comprehensive overview of inflammasomes with an emphasis on the mechanistic principles that govern inflammasome formation. We also discuss the contributions of inflammasome activation to health and disease.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1313-1344"},"PeriodicalIF":19.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01354-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1038/s41423-025-01347-x
Cecilia Ciancaglini, Silvia Santopolo, Stefania Martini, Francesca Scordamaglia, Giuseppe Pietropaolo, Mattia Laffranchi, Giuseppe Sciumè, Guido Ferlazzo, Paola Vacca, Lorenzo Moretta, Linda Quatrini
Chronic inflammation can induce lymphocyte dysfunction, which is characterized by the expression of inhibitory immune checkpoints. For type 2 innate lymphoid cells (ILC2s), the acquisition of a state of hyporesponsiveness associated with PD-1 expression has been reported in severe allergic inflammation. However, the regulation of ILC2 reactivity in the context of cancer is less clear. The contribution of ILC2s to the antitumor immune response depends, indeed, on the type of tumor and the distinct cellular interplay within the microenvironment. Here, we show that ILC2s in malignant pleural effusions express the immune checkpoints PD-1 and CTLA-4. An in vitro model of the ILC2‒macrophage interaction demonstrated that this crosstalk is responsible for driving CTLA-4 expression and limiting ILC2 activation. Thus, by preventing ILC2 exhaustion, macrophages maintain ILC2 responsiveness to signals from the tissue. These results reveal that, unlike PD-1 expression, CTLA-4 expression on ILC2s is associated with the maintenance of a reactive state during chronic inflammation in the tumor microenvironment.
{"title":"Macrophages regulate PD-1 and CTLA-4 expression on ILC2s and their responsiveness in the tumor microenvironment","authors":"Cecilia Ciancaglini, Silvia Santopolo, Stefania Martini, Francesca Scordamaglia, Giuseppe Pietropaolo, Mattia Laffranchi, Giuseppe Sciumè, Guido Ferlazzo, Paola Vacca, Lorenzo Moretta, Linda Quatrini","doi":"10.1038/s41423-025-01347-x","DOIUrl":"10.1038/s41423-025-01347-x","url":null,"abstract":"Chronic inflammation can induce lymphocyte dysfunction, which is characterized by the expression of inhibitory immune checkpoints. For type 2 innate lymphoid cells (ILC2s), the acquisition of a state of hyporesponsiveness associated with PD-1 expression has been reported in severe allergic inflammation. However, the regulation of ILC2 reactivity in the context of cancer is less clear. The contribution of ILC2s to the antitumor immune response depends, indeed, on the type of tumor and the distinct cellular interplay within the microenvironment. Here, we show that ILC2s in malignant pleural effusions express the immune checkpoints PD-1 and CTLA-4. An in vitro model of the ILC2‒macrophage interaction demonstrated that this crosstalk is responsible for driving CTLA-4 expression and limiting ILC2 activation. Thus, by preventing ILC2 exhaustion, macrophages maintain ILC2 responsiveness to signals from the tissue. These results reveal that, unlike PD-1 expression, CTLA-4 expression on ILC2s is associated with the maintenance of a reactive state during chronic inflammation in the tumor microenvironment.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1491-1505"},"PeriodicalIF":19.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01347-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1038/s41423-025-01340-4
Marc P. Hübner, Dennis de Coninck, Benjamin Lenz, Jayagopi Surendar, Marianne Koschel, Narcisse Victor Tchamatchoua Gandjui, Beng Amuam Andrew, Lucy Cho Nchang, Anita Obi Bate Ebob, Fanny fri Fombad, Lisa Marie Springer, Lars Eppe, Frank A. Schildberg, Samuel Wanji, Achim Hoerauf, Alexander Pfeifer, Indulekha Karunakaran
Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the other hand, recombinant IL-9 (rIL-9) treatment reversed insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and insulin tolerance, defective insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELMα+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1β and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves insulin signaling by inhibiting NLRP3-induced inflammation.
{"title":"The role of the IL-9‒NLRP3 axis in insulin resistance and adipose tissue inflammation during diet-induced obesity","authors":"Marc P. Hübner, Dennis de Coninck, Benjamin Lenz, Jayagopi Surendar, Marianne Koschel, Narcisse Victor Tchamatchoua Gandjui, Beng Amuam Andrew, Lucy Cho Nchang, Anita Obi Bate Ebob, Fanny fri Fombad, Lisa Marie Springer, Lars Eppe, Frank A. Schildberg, Samuel Wanji, Achim Hoerauf, Alexander Pfeifer, Indulekha Karunakaran","doi":"10.1038/s41423-025-01340-4","DOIUrl":"10.1038/s41423-025-01340-4","url":null,"abstract":"Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the other hand, recombinant IL-9 (rIL-9) treatment reversed insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and insulin tolerance, defective insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELMα+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1β and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves insulin signaling by inhibiting NLRP3-induced inflammation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1478-1490"},"PeriodicalIF":19.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01340-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-17DOI: 10.1038/s41423-025-01343-1
Yang Wang, Yukun Guan, Dechun Feng, Luca Maccioni, Maria A. Parra, Brandon Peiffer, Bryan Mackowiak, Takashige Kuwabara, Kiyoshi Mori, Masashi Mukoyama, Ramon Bataller, Zhaoli Sun, Bin Gao
Patients with alcohol-associated cirrhosis (AC) may develop severe alcohol-associated hepatitis (sAH), a disease with high short-term mortality. Our previous studies demonstrated that sAH, but not AC livers, are infiltrated with a high number of self-sustaining IL-8+ neutrophils that likely drive the transition from AC to sAH. Monocyte-derived macrophages (MoMFs) also infiltrate the liver in sAH, but their roles remain largely obscure. In the present study, we characterized liver macrophages in human liver explants from sAH and AC patients. Our data revealed a marked reduction in Kupffer cells, whereas MoMFs were increased in sAH and AC. Single-cell RNA-Seq analyses revealed several populations in both AC and sAH, including C1Q+, S100A8+, APOE+, TNF+ and VSIG4+ macrophages, with sAH containing unique C1Q+ macrophages potentially playing a role in removing apoptotic neutrophils in sAH. C1Q+ macrophages also express many genes involved in phagocytosis and proinflammatory and anti-inflammatory functions, suggesting that C1Q+ macrophages have diverse functions in sAH. The roles of C1Q, S100A8, and APOE were further examined in experimental models of alcohol-induced liver injury. Our data revealed that C1q KO mice and macrophage-specific S100a8 KO mice presented similar alcohol-induced liver injury and hepatic neutrophil infiltration, while Apoe KO mice developed much more severe liver injury than did WT mice following chronic-plus-binge ethanol challenge. Taken together, sAH and AC are infiltrated with multiple populations of macrophages that perform diverse functions to drive chronic disease progression. Unique C1Q+ macrophages in sAH play a compensatory role in removing dead cells but may also promote inflammation in sAH.
{"title":"Infiltrating macrophages replace Kupffer cells and play diverse roles in severe alcohol-associated hepatitis","authors":"Yang Wang, Yukun Guan, Dechun Feng, Luca Maccioni, Maria A. Parra, Brandon Peiffer, Bryan Mackowiak, Takashige Kuwabara, Kiyoshi Mori, Masashi Mukoyama, Ramon Bataller, Zhaoli Sun, Bin Gao","doi":"10.1038/s41423-025-01343-1","DOIUrl":"10.1038/s41423-025-01343-1","url":null,"abstract":"Patients with alcohol-associated cirrhosis (AC) may develop severe alcohol-associated hepatitis (sAH), a disease with high short-term mortality. Our previous studies demonstrated that sAH, but not AC livers, are infiltrated with a high number of self-sustaining IL-8+ neutrophils that likely drive the transition from AC to sAH. Monocyte-derived macrophages (MoMFs) also infiltrate the liver in sAH, but their roles remain largely obscure. In the present study, we characterized liver macrophages in human liver explants from sAH and AC patients. Our data revealed a marked reduction in Kupffer cells, whereas MoMFs were increased in sAH and AC. Single-cell RNA-Seq analyses revealed several populations in both AC and sAH, including C1Q+, S100A8+, APOE+, TNF+ and VSIG4+ macrophages, with sAH containing unique C1Q+ macrophages potentially playing a role in removing apoptotic neutrophils in sAH. C1Q+ macrophages also express many genes involved in phagocytosis and proinflammatory and anti-inflammatory functions, suggesting that C1Q+ macrophages have diverse functions in sAH. The roles of C1Q, S100A8, and APOE were further examined in experimental models of alcohol-induced liver injury. Our data revealed that C1q KO mice and macrophage-specific S100a8 KO mice presented similar alcohol-induced liver injury and hepatic neutrophil infiltration, while Apoe KO mice developed much more severe liver injury than did WT mice following chronic-plus-binge ethanol challenge. Taken together, sAH and AC are infiltrated with multiple populations of macrophages that perform diverse functions to drive chronic disease progression. Unique C1Q+ macrophages in sAH play a compensatory role in removing dead cells but may also promote inflammation in sAH.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1262-1275"},"PeriodicalIF":19.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01343-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Communication between group 3 innate lymphoid cells (ILC3) and other immune cells, as well as intestinal epithelial cells, is pivotal in regulating intestinal inflammation. This study, for the first time, underscores the importance of crosstalk between intestinal endothelial cells (ECs) and ILC3. Our single-cell transcriptome analysis combined with protein expression detection revealed that ECs significantly increased the population of interleukin (IL)-22+ ILC3 through interactions mediated by endothelin-1 (ET-1) and its receptor endothelin A receptor (EDNRA). Genetic deficiency of EDNRA reduces the proportion of NKp46+ ILC3 and impairs IL-22 production in a T-cell-independent, cell-intrinsic manner, leading to increased intestinal inflammation. Mechanistically, the ET-1–EDNRA axis modulates hypoxia-inducible factor 1 alpha (HIF-1α) through protein kinase B (AKT) signaling, supporting metabolic adaptation toward glycolysis and providing protection against colitis. Moreover, restoring HIF-1α expression or providing exogenous lactate can alleviate colitis associated with EDNRA deficiency and ILC3 glycolytic dysfunction. These findings underscore the importance of communication between intestinal ECs and ILC3 via the ET-1–EDNRA axis in metabolic adaptation processes within ILC3 and maintaining intestinal homeostasis.
{"title":"Endothelial cell–ILC3 crosstalk via the ET-1/EDNRA axis promotes NKp46+ILC3 glycolysis to alleviate intestinal inflammation","authors":"Xinyao Li, Yimin Chen, Junyu He, Jian Tang, Chunling Chen, Liyun Meng, Yizhuang Lu, Xiaoming Lyu, Yuxiong Guo, Yumei He","doi":"10.1038/s41423-025-01345-z","DOIUrl":"10.1038/s41423-025-01345-z","url":null,"abstract":"Communication between group 3 innate lymphoid cells (ILC3) and other immune cells, as well as intestinal epithelial cells, is pivotal in regulating intestinal inflammation. This study, for the first time, underscores the importance of crosstalk between intestinal endothelial cells (ECs) and ILC3. Our single-cell transcriptome analysis combined with protein expression detection revealed that ECs significantly increased the population of interleukin (IL)-22+ ILC3 through interactions mediated by endothelin-1 (ET-1) and its receptor endothelin A receptor (EDNRA). Genetic deficiency of EDNRA reduces the proportion of NKp46+ ILC3 and impairs IL-22 production in a T-cell-independent, cell-intrinsic manner, leading to increased intestinal inflammation. Mechanistically, the ET-1–EDNRA axis modulates hypoxia-inducible factor 1 alpha (HIF-1α) through protein kinase B (AKT) signaling, supporting metabolic adaptation toward glycolysis and providing protection against colitis. Moreover, restoring HIF-1α expression or providing exogenous lactate can alleviate colitis associated with EDNRA deficiency and ILC3 glycolytic dysfunction. These findings underscore the importance of communication between intestinal ECs and ILC3 via the ET-1–EDNRA axis in metabolic adaptation processes within ILC3 and maintaining intestinal homeostasis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1459-1477"},"PeriodicalIF":19.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-10DOI: 10.1038/s41423-025-01346-y
Yacun Chen, Sulan Yu, Philip Hei Li, Haozhen Yan, Jing Xie, Iris Yanki Tang, Hongyun Cheng, Xiang Lin
Type I interferon (IFN-I) is highly prevalent in autoimmune disorders and is intricately involved in disease pathogenesis, including Sjögren’s disease (SjD), also known as Sjögren’s syndrome. Although the T follicular helper (Tfh) cell response has been shown to drive SjD development in a mouse model of experimental Sjögren’s syndrome (ESS), the connection between IFN-I and the Tfh cell response remains unclear. As the activation of stimulator of interferon genes (STING) induces IFN-I production, we first demonstrated that mice deficient in STING or IFN-I signaling presented diminished Tfh cells and were completely resistant to ESS development. However, the STING–IFN-I axis does not directly influence Tfh cell differentiation. Instead, IFN-I signaling in B cells was essential for mounting Tfh cell responses, as evidenced in Cd19CreIfnar1flox mice, which also showed resistance to ESS development. Mechanistic analyses revealed that IFN-I drove CXCR5 expression in innate-like marginal zone B cells via the MEKK3–OCT2 axis, facilitating their migration into the follicular area. Additionally, IFN-I promoted interleukin-6 production in B cells via the MEKK3–ERK5 axis, resulting in hyperactive Tfh cell responses. In SjD patients, STING activation was predominantly observed in circulating CD14+ monocytes and was positively correlated with disease activity and effector T-cell responses. Pharmaceutical inhibition of either STING or IFNAR1 yielded moderate improvements in ESS mice with chronic inflammation, but combination therapy markedly improved outcomes and led to signs of disease remission. Our findings elucidate a novel mechanism by which IFN-I bridges innate and Tfh cell responses, suggesting new therapeutic avenues for SjD and related autoimmune disorders.
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