Pub Date : 2025-11-12DOI: 10.1038/s41423-025-01367-7
Jueun Oh, Yun-Ho Hwang, Jihye Lee, Cheong Seok, SuHyeon Oh, Hye Yoon Kim, Nabukenya Mariam, Jaeyoung Ahn, GyeongJu Yu, Jaewoo Park, Hayeon Kim, Suhyun Kim, Seyun Shin, Min-Chul Jung, Jinwoo Gil, Joo Sang Lee, Young Ki Choi, Dokeun Kim, Daesik Kim, You-Jin Kim, SangJoon Lee
Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.
猴痘是由猴痘病毒（MPXV）引起的人畜共患疾病，具有重大的全球公共卫生影响。炎性小体是先天免疫系统的重要组成部分，检测病原体并触发感染细胞死亡以消除有害物质。然而，MPXV感染过程中控制炎症小体激活的精确分子机制在很大程度上仍不清楚。通过crispr敲除细胞质先天免疫传感器筛选，我们确定AIM2是炎症小体中MPXV的传感器，这是炎症细胞死亡的触发因素。在机制上，AIM2与必需的细胞死亡分子，包括ASC和caspase-1 （CASP1）形成复合物，而不与RIPK3或CASP8相互作用。ASC、CASP1或gasdermin D （GSDMD）的缺失减少了MPXV感染后的细胞死亡，而GSDME、CASP3、CASP6、CASP7、CASP9、RIPK3或MLKL的缺失则没有这种作用。在感染细胞中主要观察到焦亡细胞死亡，而凋亡和坏死信号通路主要在未感染的旁观者细胞中激活。此外，我们发现转录因子IRF1作为AIM2的上游调节因子，控制AIM2依赖性细胞死亡。在涉及感染MPXV的aim2缺陷小鼠的实验中，我们观察到促炎细胞因子减少，多种炎症细胞死亡途径和白细胞迁移，最终导致病毒传播增加。CAST/EiJ小鼠在8天内死于高剂量MPXV感染，而AIM2抑制提高了存活率，用AIM2抑制剂治疗的小鼠中有10%存活。在低剂量感染模型中，AIM2抑制降低了IL-1β和IL-18的产生、LDH释放和组织病理。这些发现强调了AIM2介导的炎性小体激活的关键作用，以及多种程序性细胞死亡途径，在形成MPXV感染的先天免疫反应中，为开发针对AIM2和更广泛的猴痘先天免疫反应的治疗策略提供了有价值的见解。
{"title":"AIM2 drives inflammatory cell death and monkeypox pathogenesis","authors":"Jueun Oh, Yun-Ho Hwang, Jihye Lee, Cheong Seok, SuHyeon Oh, Hye Yoon Kim, Nabukenya Mariam, Jaeyoung Ahn, GyeongJu Yu, Jaewoo Park, Hayeon Kim, Suhyun Kim, Seyun Shin, Min-Chul Jung, Jinwoo Gil, Joo Sang Lee, Young Ki Choi, Dokeun Kim, Daesik Kim, You-Jin Kim, SangJoon Lee","doi":"10.1038/s41423-025-01367-7","DOIUrl":"10.1038/s41423-025-01367-7","url":null,"abstract":"Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1615-1628"},"PeriodicalIF":19.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01367-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502474","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}
The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells. It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs. Here, we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells, a process regulated by hepatic stellate cells. Mechanistically, activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33, thereby maintaining the survival and immunosuppressive function of these neutrophils. The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation of β-oxidation and the stimulation of protumorigenic eicosanoid synthesis. In mouse models, targeting IL33 blocked neutrophil lipid synthesis, decreased the colonization of colorectal cancer cells in the liver, and enhanced the efficacy of immunotherapy. Overall, our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis. Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.
{"title":"IL33-induced lipid droplet formation in mature low-density neutrophils drives colorectal cancer liver metastasis","authors":"Yuchen Zhang, Suyue Yu, Dina Yeernuer, Wangyi Liu, Zhuoqing Xu, Wenqing Feng, Zeping Lv, Xuanhao Liu, Peiqi Tan, Minhua Zheng, Yaping Zong, Aiguo Lu, Jingkun Zhao","doi":"10.1038/s41423-025-01365-9","DOIUrl":"10.1038/s41423-025-01365-9","url":null,"abstract":"The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells. It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs. Here, we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells, a process regulated by hepatic stellate cells. Mechanistically, activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33, thereby maintaining the survival and immunosuppressive function of these neutrophils. The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation of β-oxidation and the stimulation of protumorigenic eicosanoid synthesis. In mouse models, targeting IL33 blocked neutrophil lipid synthesis, decreased the colonization of colorectal cancer cells in the liver, and enhanced the efficacy of immunotherapy. Overall, our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis. Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1598-1614"},"PeriodicalIF":19.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01365-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488121","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}
Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase–stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.
{"title":"Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma","authors":"Si-Wei Wang, Wei-Feng Hong, Yi-Lan Huang, Yi-Min Zheng, Qiu-Yi Zheng, Jun-Jie Cheng, Bu-Fu Tang, Gen-Wen Chen, Bu-Gang Liang, Jia-Cheng Lu, Li Yuan, Shu-Jung Hsu, Yang Zhang, Xiao-Bin Zheng, Zhao-Chong Zeng, Jian Zhou, Jia Fan, Ai-Wu Ke, Chao Gao, Shi-Suo Du","doi":"10.1038/s41423-025-01351-1","DOIUrl":"10.1038/s41423-025-01351-1","url":null,"abstract":"Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase–stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1549-1566"},"PeriodicalIF":19.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444047","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 : 2025-10-29DOI: 10.1038/s41423-025-01361-z
Ai Li, Dengfeng Kang, Zhongsheng Feng, Haifeng Lian, Xiang Gao, Xiaohan Wu, Han Gao, Xiaoyu Li, Fushun Kou, Jian Lin, Jinghan Hua, Long Ju, Zixuan Xu, Pingchang Yang, Xue Li, Zhanju Liu
YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), yet its role in the pathogenesis of IBD, particularly in regulating immune responses in the gut mucosa, remains elusive. In this study, we demonstrated that YDJC expression is downregulated in inflamed mucosa, particularly in the CD4+ T cells of IBD patients, and that Ydjc deficiency promotes CD4+ T-cell proliferation and Th1 cell differentiation, thereby exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed that Ydjc-/-CD4+ T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis. Consistently, treatment with key enzyme inhibitors targeting cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly suppressed CD4+ T-cell proliferation and Th1 cell differentiation, thereby alleviating colitis in Ydjc-/- mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., Hmgcr, Hmgcs1, and Cyp51). Therefore, our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation, suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.
{"title":"YDJC restrains Th1 cell differentiation by blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal inflammation in inflammatory bowel disease","authors":"Ai Li, Dengfeng Kang, Zhongsheng Feng, Haifeng Lian, Xiang Gao, Xiaohan Wu, Han Gao, Xiaoyu Li, Fushun Kou, Jian Lin, Jinghan Hua, Long Ju, Zixuan Xu, Pingchang Yang, Xue Li, Zhanju Liu","doi":"10.1038/s41423-025-01361-z","DOIUrl":"10.1038/s41423-025-01361-z","url":null,"abstract":"YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), yet its role in the pathogenesis of IBD, particularly in regulating immune responses in the gut mucosa, remains elusive. In this study, we demonstrated that YDJC expression is downregulated in inflamed mucosa, particularly in the CD4+ T cells of IBD patients, and that Ydjc deficiency promotes CD4+ T-cell proliferation and Th1 cell differentiation, thereby exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed that Ydjc-/-CD4+ T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis. Consistently, treatment with key enzyme inhibitors targeting cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly suppressed CD4+ T-cell proliferation and Th1 cell differentiation, thereby alleviating colitis in Ydjc-/- mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., Hmgcr, Hmgcs1, and Cyp51). Therefore, our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation, suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"15-30"},"PeriodicalIF":19.8,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400121","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 : 2025-10-27DOI: 10.1038/s41423-025-01353-z
Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen
{"title":"Not marginal but central: type I interferons unleash marginal zone B cells in Sjögren’s disease","authors":"Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen","doi":"10.1038/s41423-025-01353-z","DOIUrl":"10.1038/s41423-025-01353-z","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1642-1644"},"PeriodicalIF":19.8,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376559","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 : 2025-10-27DOI: 10.1038/s41423-025-01357-9
Hamida Hammad, Engi Ahmed, Bart N. Lambrecht
Type 2high asthma, which accounts for the majority of asthma cases, is driven by Th2 cells that produce cytokines such as IL-4, IL-5, and IL-13. These cytokines promote several features of the disease, including eosinophilia, IgE production, bronchial hyperresponsiveness (BHR), mucus hypersecretion, and susceptibility to exacerbations. In contrast, type 2low asthma is characterized by the presence of neutrophils and reduced responsiveness to corticosteroids. In recent years, advances in our understanding of the distinct mechanisms at play in each asthma endotype have paved the way for the development of targeted therapies tailored to specific patient profiles. In this review, we first explore the underlying immunological mechanisms of various asthma endotypes. We also provide an overview of the different types of immunotherapies currently available to asthmatic patients and their clinical efficacy. Finally, we highlight emerging therapeutic strategies that hold promise for improving asthma management in the future.
{"title":"Immunotherapy for asthma","authors":"Hamida Hammad, Engi Ahmed, Bart N. Lambrecht","doi":"10.1038/s41423-025-01357-9","DOIUrl":"10.1038/s41423-025-01357-9","url":null,"abstract":"Type 2high asthma, which accounts for the majority of asthma cases, is driven by Th2 cells that produce cytokines such as IL-4, IL-5, and IL-13. These cytokines promote several features of the disease, including eosinophilia, IgE production, bronchial hyperresponsiveness (BHR), mucus hypersecretion, and susceptibility to exacerbations. In contrast, type 2low asthma is characterized by the presence of neutrophils and reduced responsiveness to corticosteroids. In recent years, advances in our understanding of the distinct mechanisms at play in each asthma endotype have paved the way for the development of targeted therapies tailored to specific patient profiles. In this review, we first explore the underlying immunological mechanisms of various asthma endotypes. We also provide an overview of the different types of immunotherapies currently available to asthmatic patients and their clinical efficacy. Finally, we highlight emerging therapeutic strategies that hold promise for improving asthma management in the future.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1521-1532"},"PeriodicalIF":19.8,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01357-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376581","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 : 2025-10-20DOI: 10.1038/s41423-025-01355-x
Yuhang Wang, Joyce Z. Gao, Prajwal Gurung, Sarah P. Short, Yiqin Xiong, Scott W. Canna, Zizhen Kang
Inflammasomes, particularly NLRC4, play crucial roles in immune responses to intracellular bacterial infections. However, gain-of-function mutations in NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). AIFEC patients who survive infancy typically have no further intestinal symptoms but retain susceptibility to macrophage activation syndrome (MAS). However, existing mouse models do not adequately replicate the inflammation observed in AIFEC patients. To better understand this, we developed a mouse model capable of conditional expression of the activating V341A mutation in NLRC4 (NLRC4-V341A KI). Global conversion to NLRC4-V341A at the germline resulted in symptoms closely mirroring those of human AIFEC, including severe infantile enterocolitis characterized by heightened intestinal inflammation, disrupted gut epithelium, compromised intestinal barrier integrity, severe diarrhea, and mortality within 10 days post-natally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1β, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, conditional conversion to NLRC4-V341A in adulthood caused systemic autoinflammation with only mild enterocolitis, mirroring AIFEC patients. Using this model, we demonstrated that IL-18 and TNF blockade effectively ameliorated AIFEC disease symptoms. Unexpectedly, glucose supplementation has emerged as a promising therapeutic strategy. These findings advance our understanding of AIFEC and illuminate the ways in which inflammasome activation contributes to very early onset inflammatory bowel disease (VEO-IBD) in the developing gut.
{"title":"An animal model of NLRC4-associated autoinflammation and infantile enterocolitis reveals novel therapeutic strategies","authors":"Yuhang Wang, Joyce Z. Gao, Prajwal Gurung, Sarah P. Short, Yiqin Xiong, Scott W. Canna, Zizhen Kang","doi":"10.1038/s41423-025-01355-x","DOIUrl":"10.1038/s41423-025-01355-x","url":null,"abstract":"Inflammasomes, particularly NLRC4, play crucial roles in immune responses to intracellular bacterial infections. However, gain-of-function mutations in NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). AIFEC patients who survive infancy typically have no further intestinal symptoms but retain susceptibility to macrophage activation syndrome (MAS). However, existing mouse models do not adequately replicate the inflammation observed in AIFEC patients. To better understand this, we developed a mouse model capable of conditional expression of the activating V341A mutation in NLRC4 (NLRC4-V341A KI). Global conversion to NLRC4-V341A at the germline resulted in symptoms closely mirroring those of human AIFEC, including severe infantile enterocolitis characterized by heightened intestinal inflammation, disrupted gut epithelium, compromised intestinal barrier integrity, severe diarrhea, and mortality within 10 days post-natally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1β, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, conditional conversion to NLRC4-V341A in adulthood caused systemic autoinflammation with only mild enterocolitis, mirroring AIFEC patients. Using this model, we demonstrated that IL-18 and TNF blockade effectively ameliorated AIFEC disease symptoms. Unexpectedly, glucose supplementation has emerged as a promising therapeutic strategy. These findings advance our understanding of AIFEC and illuminate the ways in which inflammasome activation contributes to very early onset inflammatory bowel disease (VEO-IBD) in the developing gut.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1567-1580"},"PeriodicalIF":19.8,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01355-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336450","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 : 2025-10-14DOI: 10.1038/s41423-025-01358-8
Cecilia Garlanda, Irene Di Ceglie, Sebastien Jaillon
Interleukin-1 (IL-1) was the first interleukin identified as a potent proinflammatory and multifunctional molecule involved in innate immune responses against microbes, as well as in conditions of tissue injury associated with infections and sterile conditions. IL-1 is part of a large system, the IL-1 system, comprising a family of ligands that act as agonists, receptor antagonists, and anti-inflammatory cytokines, as well as a family of receptors that includes signaling receptor complexes, decoy receptors and negative regulators. All the members of the IL-1 system are involved in inflammatory diseases, innate and adaptive immune responses, conditions associated with dysmetabolism, and cancer by affecting both the tumor microenvironment and cancer cells. The deregulated or excessive activation of several pathways associated with the IL-1 system may lead to detrimental inflammatory or immune reactions, including autoinflammatory, autoimmune, infectious and degenerative diseases. The negative regulation of the IL-1 system mediated by antagonists, decoy receptors, scavengers, and dominant-negative molecules plays nonredundant roles in controlling these conditions. Owing to the central role of IL-1 in the pathogenesis of inflammation-driven diseases, IL-1 blocking agents are approved for clinical use in several inflammatory conditions, and inhibitory agents for other members of the family are under development. Here, the complexity of the IL-1 system, the involvement of its different members in inflammation-driven diseases, and the therapeutic approaches to target members of pathways associated with these conditions are presented and discussed.
{"title":"IL-1 family cytokines in inflammation and immunity","authors":"Cecilia Garlanda, Irene Di Ceglie, Sebastien Jaillon","doi":"10.1038/s41423-025-01358-8","DOIUrl":"10.1038/s41423-025-01358-8","url":null,"abstract":"Interleukin-1 (IL-1) was the first interleukin identified as a potent proinflammatory and multifunctional molecule involved in innate immune responses against microbes, as well as in conditions of tissue injury associated with infections and sterile conditions. IL-1 is part of a large system, the IL-1 system, comprising a family of ligands that act as agonists, receptor antagonists, and anti-inflammatory cytokines, as well as a family of receptors that includes signaling receptor complexes, decoy receptors and negative regulators. All the members of the IL-1 system are involved in inflammatory diseases, innate and adaptive immune responses, conditions associated with dysmetabolism, and cancer by affecting both the tumor microenvironment and cancer cells. The deregulated or excessive activation of several pathways associated with the IL-1 system may lead to detrimental inflammatory or immune reactions, including autoinflammatory, autoimmune, infectious and degenerative diseases. The negative regulation of the IL-1 system mediated by antagonists, decoy receptors, scavengers, and dominant-negative molecules plays nonredundant roles in controlling these conditions. Owing to the central role of IL-1 in the pathogenesis of inflammation-driven diseases, IL-1 blocking agents are approved for clinical use in several inflammatory conditions, and inhibitory agents for other members of the family are under development. Here, the complexity of the IL-1 system, the involvement of its different members in inflammation-driven diseases, and the therapeutic approaches to target members of pathways associated with these conditions are presented and discussed.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1345-1362"},"PeriodicalIF":19.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01358-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291322","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}
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