The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injury.
The immunobiology of FXR has attracted significant attention in immune regulation and innate immunity. We have studied the mechanism of action of FXR activation on two models of acute hepatitis, inflammation mediated by Con A and α-GalCer and focused on the interactions of FXR activation and expression of PIR-B, both in vivo and in vitro using luciferase reporter and CHIP assays. In addition, based upon our data, we studied the role of FXR activation on the immunobiology of myeloid-derived suppressor cells (MDSCs). Importantly, we report herein that FXR activation reduces the inflammatory insult induced by either α-GalCer or Con A; such treatment expands CD11b(+)Ly6C(+) MDSCs. The protective effect of FXR activation is dependent on expansion of MDSCs, particularly liver CD11b(+)Ly6C(high) cells. Indeed, FXR activation enhances the suppressor function of MDSCs through upregulation of PIR-B by binding the PIR-B promoter. FXR activation drives the accumulation of MDSCs to liver through upregulation of S100A8. FXR activation facilitates homing and function of MDSCs, which function as a critical negative feedback loop in immune-mediated liver injury. The novel mechanisms defined herein emphasize not only the importance of liver lymphoid subpopulations, but also the potential roles of modulating FXR in autoimmune liver disease.
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Haiyan
H
Zhang
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Yuan
Y
Liu
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Zhaolian
Z
Bian
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Shanshan
S
Huang
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Xiaofeng
X
Han
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Zhengrui
Z
You
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Qixia
Q
Wang
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Dekai
D
Qiu
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Qi
Q
Miao
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
Yanshen
Y
Peng
Shanghai Institute of Endocrinology and Metabolism, Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China.
Xiaoying
X
Li
Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Pietro
P
Invernizzi
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China. Electronic address: maxiongmd@hotmail.com.
Xiong
X
Ma
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology; D003208:Concanavalin A / Q000009:adverse effects / Q000494:pharmacology; D005699:Galactosylceramides / Q000633:toxicity; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens / Q000009:adverse effects / Q000494:pharmacology; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D000099150:Receptor, Farnesoid X-Activated
D000950:Antigens, Ly; D039481:CD11b Antigen; D040501:Calgranulin A; D003208:Concanavalin A; D005699:Galactosylceramides; D008934:Mitogens; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D000099150:Receptor, Farnesoid X-Activated; C494192:Ly-6C antigen, mouse; C105949:Pirb protein, mouse; C086145:S100a8 protein, mouse; C493154:alpha-galactosylceramide
Autoimmunity; FXR activation; Lymphoid subpopulations; Myeloid-derived suppressor cells