{"title":"Consuelo H. Wilkins receives the 2025 ASCI/Louis W. Sullivan, MD, Award.","authors":"","doi":"10.1172/jci199942","DOIUrl":"https://doi.org/10.1172/jci199942","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hui Jin,Saoirse Holland,Alok Jha,Gaifeng Ma,Jingsong Li,Atsushi Murao,Monowar Aziz,Ping Wang
Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4+ neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA-binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4+ neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4+ neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway's critical role in DLL4+ neutrophil-mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.
{"title":"DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.","authors":"Hui Jin,Saoirse Holland,Alok Jha,Gaifeng Ma,Jingsong Li,Atsushi Murao,Monowar Aziz,Ping Wang","doi":"10.1172/jci194310","DOIUrl":"https://doi.org/10.1172/jci194310","url":null,"abstract":"Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4+ neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA-binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4+ neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4+ neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway's critical role in DLL4+ neutrophil-mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome instability is most commonly caused by replication stress, which also renders cancer cells extremely vulnerable once their response to replication stress is impeded. Topoisomerase II binding protein 1 (TOPBP1), an allosteric activator of ataxia telangiectasia and Rad3-related kinase (ATR), coordinates ATR in replication stress response and has emerged as a potential therapeutic target for tumors. Here, we identify auranofin, the FDA-approved drug for rheumatoid arthritis, as a lead compound capable of binding to the BRCT 7-8 domains and blocking TOPBP1 interaction with PHF8 and FANCJ. The liquid-liquid phase separation of TOPBP1 is also disrupted by auranofin. Through targeting these TOPBP1-nucleated molecular machineries, auranofin leads to an accumulation of replication defects by impairing ATR activation and attenuating replication protein A loading on perturbed replication forks, and it shows significant anti-breast tumor activity in combination with a PARP inhibitor. This study provides mechanistic insights into how auranofin challenges replication integrity and expands the application of this FDA-approved drug in breast tumor intervention.
{"title":"Auranofin attenuates TOPBP1-mediated ATR replication stress response and improves chemotherapeutic response in breast tumor models.","authors":"Shuai Ma,Yingying Han,Rui Gu,Qi Chen,Qiushi Guo,Yuan Yue,Cheng Cao,Ling Liu,Zhenzhen Yang,Yan Qin,Ying Yang,Kai Zhang,Fei Liu,Lin Liu,Na Yang,Jihui Hao,Jie Yang,Zhi Yao,Xiaoyun Mao,Lei Shi","doi":"10.1172/jci180106","DOIUrl":"https://doi.org/10.1172/jci180106","url":null,"abstract":"Genome instability is most commonly caused by replication stress, which also renders cancer cells extremely vulnerable once their response to replication stress is impeded. Topoisomerase II binding protein 1 (TOPBP1), an allosteric activator of ataxia telangiectasia and Rad3-related kinase (ATR), coordinates ATR in replication stress response and has emerged as a potential therapeutic target for tumors. Here, we identify auranofin, the FDA-approved drug for rheumatoid arthritis, as a lead compound capable of binding to the BRCT 7-8 domains and blocking TOPBP1 interaction with PHF8 and FANCJ. The liquid-liquid phase separation of TOPBP1 is also disrupted by auranofin. Through targeting these TOPBP1-nucleated molecular machineries, auranofin leads to an accumulation of replication defects by impairing ATR activation and attenuating replication protein A loading on perturbed replication forks, and it shows significant anti-breast tumor activity in combination with a PARP inhibitor. This study provides mechanistic insights into how auranofin challenges replication integrity and expands the application of this FDA-approved drug in breast tumor intervention.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"256 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
During the progression of acute myeloid leukemia (AML), extramedullary hematopoiesis (EMH) compensates for impaired bone marrow hematopoiesis. However, the specific cellular dynamics of EMH and its influence on AML progression remain poorly understood. In this study, we identified a substantial expansion of the CD81+ erythroblast subpopulation (CD81+ Erys) in the spleens of AML mice, which promoted AML cell proliferation and reduced survival. Mechanistically, CD81+ Erys secrete elevated levels of macrophage migration-inhibitory factor (MIF), which interacted with the CD74 receptor on AML cells, activating the mTORC1 signaling pathway and upregulating Egln3. Consequently, AML cells cocultured with CD81+ Erys exhibited reprogrammed phospholipid metabolism, characterized by an increased phospholipid-to-lysophospholipid ratio. Modulating this metabolic shift, either by supplementing exogenous lysophospholipids or depleting Egln3 in AML cells, restored the phospholipid balance and mitigated the protumorigenic effects induced by CD81+ Erys. Overall, our findings elucidate the molecular crosstalk between erythroblasts and AML cells, extend our insights into the mechanisms driving AML progression, and suggest potential therapeutic strategies.
{"title":"Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism.","authors":"Yue Li,Jiaxuan Cao,Jingyuan Tong,Peixia Tang,Haoran Chen,Guohuan Sun,Zining Yang,Xiaoru Zhang,Fang Dong,Shangda Yang,Jie Gao,Xiangnan Zhao,Jinfa Ma,Di Wang,Lei Zhang,Lin Wang,Tao Cheng,Hui Cheng,Lihong Shi","doi":"10.1172/jci193082","DOIUrl":"https://doi.org/10.1172/jci193082","url":null,"abstract":"During the progression of acute myeloid leukemia (AML), extramedullary hematopoiesis (EMH) compensates for impaired bone marrow hematopoiesis. However, the specific cellular dynamics of EMH and its influence on AML progression remain poorly understood. In this study, we identified a substantial expansion of the CD81+ erythroblast subpopulation (CD81+ Erys) in the spleens of AML mice, which promoted AML cell proliferation and reduced survival. Mechanistically, CD81+ Erys secrete elevated levels of macrophage migration-inhibitory factor (MIF), which interacted with the CD74 receptor on AML cells, activating the mTORC1 signaling pathway and upregulating Egln3. Consequently, AML cells cocultured with CD81+ Erys exhibited reprogrammed phospholipid metabolism, characterized by an increased phospholipid-to-lysophospholipid ratio. Modulating this metabolic shift, either by supplementing exogenous lysophospholipids or depleting Egln3 in AML cells, restored the phospholipid balance and mitigated the protumorigenic effects induced by CD81+ Erys. Overall, our findings elucidate the molecular crosstalk between erythroblasts and AML cells, extend our insights into the mechanisms driving AML progression, and suggest potential therapeutic strategies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radiotherapy is a key treatment modality in many malignancies, but radiation-induced immunosuppression can undermine its outcomes and diminish the efficacy of combinatorial strategies, like radioimmunotherapy. In this issue of the JCI, Deng et al. implicate cGAS/STING signaling in the recruitment of γδ T cells that drive downstream radioresistance. Radiation-induced microparticles containing double-stranded tumor DNA led to activation of the cGAS/STING pathway in macrophages, promoting γδ T cell recruitment through CCL20 signaling. In mouse models, γδ T cell-dependent recruitment of myeloid-derived suppressor cells and T cell suppression curbed radiotherapy efficacy and drove antitumor immunity. Ablation of γδ T cells improved the efficacy of radiotherapy alone and radiotherapy combined with immune checkpoint inhibitors in mouse models, supporting further investigation of γδ T cell targeting to improve clinical outcomes with radioimmunotherapy. The findings also add complexity to the function of the cGAS/STING pathway in setting the balance between antitumor immunity and immunosuppression.
{"title":"cGAS/STING-mediated γδ T cell recruitment drives radioresistance: implications for improving radioimmunotherapy outcomes.","authors":"Brooke C Braman,David R Raleigh","doi":"10.1172/jci200465","DOIUrl":"https://doi.org/10.1172/jci200465","url":null,"abstract":"Radiotherapy is a key treatment modality in many malignancies, but radiation-induced immunosuppression can undermine its outcomes and diminish the efficacy of combinatorial strategies, like radioimmunotherapy. In this issue of the JCI, Deng et al. implicate cGAS/STING signaling in the recruitment of γδ T cells that drive downstream radioresistance. Radiation-induced microparticles containing double-stranded tumor DNA led to activation of the cGAS/STING pathway in macrophages, promoting γδ T cell recruitment through CCL20 signaling. In mouse models, γδ T cell-dependent recruitment of myeloid-derived suppressor cells and T cell suppression curbed radiotherapy efficacy and drove antitumor immunity. Ablation of γδ T cells improved the efficacy of radiotherapy alone and radiotherapy combined with immune checkpoint inhibitors in mouse models, supporting further investigation of γδ T cell targeting to improve clinical outcomes with radioimmunotherapy. The findings also add complexity to the function of the cGAS/STING pathway in setting the balance between antitumor immunity and immunosuppression.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gunnar Weninger,Haikel Dridi,Steven Reiken,Qi Yuan,Nan Zhao,Linda Groom,Jennifer Leigh,Yang Liu,Carl Tchagou,Jiayi Kang,Alexander Chang,Estefania Luna-Figueroa,Marco C Miotto,Anetta Wronska,Robert T Dirksen,Andrew R Marks
Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.
{"title":"Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation.","authors":"Gunnar Weninger,Haikel Dridi,Steven Reiken,Qi Yuan,Nan Zhao,Linda Groom,Jennifer Leigh,Yang Liu,Carl Tchagou,Jiayi Kang,Alexander Chang,Estefania Luna-Figueroa,Marco C Miotto,Anetta Wronska,Robert T Dirksen,Andrew R Marks","doi":"10.1172/jci194490","DOIUrl":"https://doi.org/10.1172/jci194490","url":null,"abstract":"Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Alexander G. Bick receives the 2025 ASCI/Seldin~Smith Award for Pioneering Research.","authors":"","doi":"10.1172/jci199946","DOIUrl":"https://doi.org/10.1172/jci199946","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"145 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carmen Oi Ning Leung,Shilpa Gurung,Katherine Po Sin Chung,Rainbow Wing Hei Leung,Martina Mang Leng Lei,Mandy Sze Man Chan,Gregory Kenneth Muliawan,Shakeel Ahmad Khan,Xue Qian Wu,Jun Yu,Hui Lian Zhu,Yin Ying Lu,Stephanie Ma,Xiaoping Wu,Ruby Lai Chong Hoo,Terence Kin Wah Lee
Metabolic dysfunction-associated steatotic liver disease-induced (MASLD-induced) hepatocellular carcinoma (HCC) is an emerging malignancy linked to excessive accumulation of adipose tissue and hepatic fat. Understanding the role of adipocytes in the development of MASLD-induced HCC is crucial. In an in vitro coculture system, differentiated adipocytes were found to enhance cancer stemness and drug resistance in HCC through paracrine signaling. Fatty acid-binding protein 4 (FABP4) was preferentially secreted by adipocytes, and recombinant FABP4 further augmented the cancer stem cell (CSC) properties of HCC cells. Notably, Fabp4-/- mice exhibited a marked delay in the progression of MASLD-HCC, which correlated with the increased HCC risk observed in MASLD patients with elevated FABP4 expression. Mass spectrometry analysis identified integrin β 1 (ITGB1) as a binding partner of FABP4. These data, together with a substantial downregulation of the Wnt/β-catenin pathway in Fabp4-/- mouse tumors, revealed that FABP4 augmented liver CSC functions by activating PI3K/AKT/β-catenin signaling via ITGB1. We developed an anti-FABP4 neutralizing antibody that successfully inhibited FABP4-driven CSC functions and suppressed MASLD-induced HCC. In conclusion, our findings indicate that adipocyte-derived FABP4 plays a critical role in the development of MASLD-induced HCC and targeting the ITGB1/PI3K/AKT/β-catenin signaling cascade may offer a promising approach to combat this aggressive disease.
{"title":"Adipocyte-derived FABP4 promotes metabolism-associated steatotic liver-induced hepatocellular carcinoma by driving ITGB1-mediated β-catenin activation.","authors":"Carmen Oi Ning Leung,Shilpa Gurung,Katherine Po Sin Chung,Rainbow Wing Hei Leung,Martina Mang Leng Lei,Mandy Sze Man Chan,Gregory Kenneth Muliawan,Shakeel Ahmad Khan,Xue Qian Wu,Jun Yu,Hui Lian Zhu,Yin Ying Lu,Stephanie Ma,Xiaoping Wu,Ruby Lai Chong Hoo,Terence Kin Wah Lee","doi":"10.1172/jci182322","DOIUrl":"https://doi.org/10.1172/jci182322","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease-induced (MASLD-induced) hepatocellular carcinoma (HCC) is an emerging malignancy linked to excessive accumulation of adipose tissue and hepatic fat. Understanding the role of adipocytes in the development of MASLD-induced HCC is crucial. In an in vitro coculture system, differentiated adipocytes were found to enhance cancer stemness and drug resistance in HCC through paracrine signaling. Fatty acid-binding protein 4 (FABP4) was preferentially secreted by adipocytes, and recombinant FABP4 further augmented the cancer stem cell (CSC) properties of HCC cells. Notably, Fabp4-/- mice exhibited a marked delay in the progression of MASLD-HCC, which correlated with the increased HCC risk observed in MASLD patients with elevated FABP4 expression. Mass spectrometry analysis identified integrin β 1 (ITGB1) as a binding partner of FABP4. These data, together with a substantial downregulation of the Wnt/β-catenin pathway in Fabp4-/- mouse tumors, revealed that FABP4 augmented liver CSC functions by activating PI3K/AKT/β-catenin signaling via ITGB1. We developed an anti-FABP4 neutralizing antibody that successfully inhibited FABP4-driven CSC functions and suppressed MASLD-induced HCC. In conclusion, our findings indicate that adipocyte-derived FABP4 plays a critical role in the development of MASLD-induced HCC and targeting the ITGB1/PI3K/AKT/β-catenin signaling cascade may offer a promising approach to combat this aggressive disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"169 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xin Huang,Min Liu,Michael V Gonzalez,Rahul Debnath,Hamideh Afzali,Yongwon Choi,Su Ah Kim,Kang I Ko,Dana T Graves
Periodontal disease, a bacterial infection affecting a large percentage of the world's population, is an important risk factor for several systemic diseases and is significantly worsened by diabetes. To investigate how diabetes exacerbates the inflammatory response to bacteria in this disease, we combined insights from murine and human studies. Through single-cell RNA sequencing, we identified a compelling hyperglycemia-driven molecular pathway: the upregulation of CD137L in dendritic cells and increased expression of its receptor, CD137, in γδ T-cells. The CD137L-CD137 axis emerged as a pivotal mediator of diabetes-induced inflammatory tissue destruction. Antibody-mediated inhibition of CD137L markedly reduced the diabetes-driven bone loss, neutrophil recruitment, expansion of γδ T-cells, and excessive infiltration by IL17A+ cells. In vitro studies further validated these findings and established that high glucose-mediated dysregulation of dendritic cells dramatically altered γδ T-cell activity in co-culture systems via CD137L. The essential role of dendritic cells as CD137L producers in vivo was definitively established through lineage-specific Akt1 deletion, which abrogated CD137L expression in these cells and reversed the adverse effects of hyperglycemia on leukocyte responses to bacterial pathogens in vivo. Conversely, activation of CD137 with an agonist in normal animals recapitulated diabetes-induced abnormalities in the inflammatory response and accelerated bone loss. These findings elucidate a key mechanism underlying diabetes-induced immune dysregulation and inflammatory damage, and point to the CD137L-CD137 pathway as a promising therapeutic target, offering potential insights into mitigating other diabetes-associated complications linked to inflammatory changes.
{"title":"Diabetes exacerbates destructive inflammation by activating theCD137L-CD137 axis in dendritic and γδ T-cells.","authors":"Xin Huang,Min Liu,Michael V Gonzalez,Rahul Debnath,Hamideh Afzali,Yongwon Choi,Su Ah Kim,Kang I Ko,Dana T Graves","doi":"10.1172/jci193289","DOIUrl":"https://doi.org/10.1172/jci193289","url":null,"abstract":"Periodontal disease, a bacterial infection affecting a large percentage of the world's population, is an important risk factor for several systemic diseases and is significantly worsened by diabetes. To investigate how diabetes exacerbates the inflammatory response to bacteria in this disease, we combined insights from murine and human studies. Through single-cell RNA sequencing, we identified a compelling hyperglycemia-driven molecular pathway: the upregulation of CD137L in dendritic cells and increased expression of its receptor, CD137, in γδ T-cells. The CD137L-CD137 axis emerged as a pivotal mediator of diabetes-induced inflammatory tissue destruction. Antibody-mediated inhibition of CD137L markedly reduced the diabetes-driven bone loss, neutrophil recruitment, expansion of γδ T-cells, and excessive infiltration by IL17A+ cells. In vitro studies further validated these findings and established that high glucose-mediated dysregulation of dendritic cells dramatically altered γδ T-cell activity in co-culture systems via CD137L. The essential role of dendritic cells as CD137L producers in vivo was definitively established through lineage-specific Akt1 deletion, which abrogated CD137L expression in these cells and reversed the adverse effects of hyperglycemia on leukocyte responses to bacterial pathogens in vivo. Conversely, activation of CD137 with an agonist in normal animals recapitulated diabetes-induced abnormalities in the inflammatory response and accelerated bone loss. These findings elucidate a key mechanism underlying diabetes-induced immune dysregulation and inflammatory damage, and point to the CD137L-CD137 pathway as a promising therapeutic target, offering potential insights into mitigating other diabetes-associated complications linked to inflammatory changes.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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