TY - JOUR
T1 - The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injury
AU - Zhang, Haiyan
AU - Liu, Yuan
AU - Bian, Zhaolian
AU - Huang, Shanshan
AU - Han, Xiaofeng
AU - You, Zhengrui
AU - Wang, Qixia
AU - Qiu, Dekai
AU - Miao, Qi
AU - Peng, Yanshen
AU - Li, Xiaoying
AU - Invernizzi, Pietro
AU - Ma, Xiong
PY - 2014
Y1 - 2014
N2 - 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 invivo and invitro 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+Ly6Chigh 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.
AB - 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 invivo and invitro 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+Ly6Chigh 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.
KW - Autoimmunity
KW - FXR activation
KW - Lymphoid subpopulations
KW - Myeloid-derived suppressor cells
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U2 - 10.1016/j.jaut.2014.02.010
DO - 10.1016/j.jaut.2014.02.010
M3 - Article
C2 - 24721598
AN - SCOPUS:84926408803
VL - 53
SP - 55
EP - 66
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - C
ER -