标题：Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice
作者：Du, Xianhong; Wu, Zhuanchang; Xu, Yong; Liu, Yuan; Liu, Wen; Wang, Tixiao; Li, Chunyang; Zhang, Cuijuan; Yi, Fan; Gao, Lifen; Lian 更多 作者机构：[Du, Xianhong; Wu, Zhuanchang; Xu, Yong; Liu, Wen; Wang, Tixiao; Yi, Fan; Gao, Lifen; Liang, Xiaohong; Ma, Chunhong] Shandong Univ, Dept Immunol, Key 更多
通讯作者：Ma, CH;Ma, CH
通讯作者地址：[Ma, CH]Shandong Univ, Dept Immunol, Key Lab Expt Teratol, Minist Educ,Sch Basic Med Sci, Jinan 250012, Shandong, Peoples R China;[Ma, CH]Shandong Uni 更多
来源：CELLULAR & MOLECULAR IMMUNOLOGY
关键词：macrophage; NASH; ROS; Tim-3
摘要：As an immune checkpoint, Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases. However, the precise roles of Tim-3 in nonalcoholic steatohepatitis (NASH) remain unstated. In the current study, we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet (MCD)-induced NASH mice. The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice, including F4/80(+)CD11b(+), F4/80(+)CD68(+), and F4/80(+)CD169(+) macrophages. Remarkably, Tim-3 knockout (KO) significantly accelerated MCD-induced liver steatosis, displaying higher serum ALT, larger hepatic vacuolation, more liver lipid deposition, and more severe liver fibrosis. Moreover, compared with wild-type C57BL/6 mice, Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2, NLRP3, and caspase-1 p20 together with increased generation of IL-1 beta and IL-18 in livers. In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species (ROS) and related downstream pro-inflammatory cytokine secretion of IL-1 beta and IL-18 in macrophages. Exogenous administration of N-Acetyl-L-cysteine (NAC), a small molecular inhibitor of ROS, remarkably suppressed caspase-1 p20 expression and IL-1 beta and IL-18 production in livers of Tim-3 KO mice, thus significantly reducing the severity of steatohepatitis induced by MCD. In conclusion, Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.