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Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

ABSTRACT: 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? 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? 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? 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.

SUBMITTER: Du X

PROVIDER: S-EPMC6828758 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

Du Xianhong X Wu Zhuanchang Z Xu Yong Y Liu Yuan Y Liu Wen W Wang Tixiao T Li Chunyang C Zhang Cuijuan C Yi Fan F Gao Lifen L Liang Xiaohong X Ma Chunhong C

Cellular & molecular immunology 20180507 11

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 N ...[more]

PMID: 29735977

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Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

Publications

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

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