OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis
Guangyong Sun,
Hua Jin,
Chunpan Zhang,
Hua Meng,
Xinyan Zhao,
Dan Wei,
Xiaojuan Ou,
Qianyi Wang,
Shuxiang Li,
Tianqi Wang,
Xiaojing Sun,
Wen Shi,
Dan Tian,
Kai Liu,
Hufeng Xu,
Yue Tian,
Xinmin Li,
Wei Guo,
Jidong Jia,
Zhongtao Zhang,
Dong Zhang
Affiliations
Guangyong Sun
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Hua Jin
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Chunpan Zhang
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Hua Meng
General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
Xinyan Zhao
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
Dan Wei
General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
Xiaojuan Ou
National Clinical Research Center for Digestive Diseases, Beijing, 100050, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
Qianyi Wang
National Clinical Research Center for Digestive Diseases, Beijing, 100050, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
Shuxiang Li
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
Tianqi Wang
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Xiaojing Sun
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Wen Shi
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Dan Tian
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Kai Liu
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Hufeng Xu
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Yue Tian
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Xinmin Li
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China
Wei Guo
General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
Jidong Jia
National Clinical Research Center for Digestive Diseases, Beijing, 100050, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, 100050, China
Zhongtao Zhang
General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; National Clinical Research Center for Digestive Diseases, Beijing, 100050, China; Corresponding author
Dong Zhang
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Clinical Research Institute, Beijing, 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, China; National Clinical Research Center for Digestive Diseases, Beijing, 100050, China; Corresponding author
Summary: Both innate and adaptive immune cells are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the crosstalk between innate and adaptive immunity is largely unknown. Here we show that compared with WT mice, OX40−/− mice exhibit decreased liver fat accumulation, lobular inflammation, and focal necrosis after feeding with diets that induce NASH. Mechanistically, OX40 deficiency suppresses Th1 and Th17 differentiation, and OX40 deficiency in T cells inhibits monocyte migration, antigen presentation, and M1 polarization. Soluble OX40 stimulation alone upregulates antigen presentation, chemokine receptor expression, and proinflammatory cytokine secretion by liver monocytes. Furthermore, plasma soluble OX40 levels are positively associated with NASH in humans, suggesting clinical relevance of the findings. In conclusion, we show a mechanism for T cell regulation of innate immune cells. OX40 is a key regulator of both intrahepatic innate and adaptive immunity, generates two-way signals, and promotes both proinflammatory monocyte and macrophage and T cell function, resulting in NASH development. : Sun et al. show that OX40 is a key molecule in the regulation of both intrahepatic innate and adaptive immunity. OX40 promotes both proinflammatory monocyte and macrophage and T cell function, resulting in NASH development and progression. These findings suggest that OX40 could serve as a diagnostic index and therapeutic target in NASH. Keywords: OX40, NAFLD, inflammation, monocyte, T cell
