The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injury

被引:34
作者
Zhang, Haiyan [1 ,2 ]
Liu, Yuan [1 ,2 ]
Bian, Zhaolian [1 ,2 ]
Huang, Shanshan [1 ,2 ]
Han, Xiaofeng [1 ,2 ]
You, Zhengrui [1 ,2 ]
Wang, Qixia [1 ,2 ]
Qiu, Dekai [1 ,2 ]
Miao, Qi [1 ,2 ]
Peng, Yanshen [1 ,2 ]
Li, Xiaoying [3 ]
Invernizzi, Pietro [4 ,5 ]
Ma, Xiong [1 ,2 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Digest Dis, Ren Ji Hosp,Div Gastroenterol & Hepatol, Shanghai 200001, Peoples R China
[2] Shanghai Jiao Tong Univ, Minist Hlth, Key Lab Gastroenterol & Hepatol, Shanghai 200001, Peoples R China
[3] Shanghai Jiao Tong Univ, Shanghai Inst Endocrinol & Metab, Shanghai Clin Ctr Endocrine & Metab Dis, Dept Endocrine & Metab Dis,Ruijin Hosp,Sch Med, Shanghai 200001, Peoples R China
[4] Humanitas Clin & Res Ctr, Liver Unit, Milan, Italy
[5] Humanitas Clin & Res Ctr, Ctr Autoimmune Liver Dis, Milan, Italy
基金
中国国家自然科学基金;
关键词
Autoimmunity; FXR activation; Lymphoid subpopulations; Myeloid-derived suppressor cells; PIR-B; TUMOR PROGRESSION; HEPATOCELLULAR-CARCINOMA; RECEPTOR; ACCUMULATION; INFLAMMATION; MICE; RESPONSES; EXPRESSION; SUBSETS;
D O I
10.1016/j.jaut.2014.02.010
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 alpha-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 alpha-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. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:55 / 66
页数:12
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