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Cell Mol Immunol. 2018 May 7. doi: 10.1038/s41423-018-0032-0. [Epub ahead of print]

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

Author information

1
Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, PR China.
2
Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
3
Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, Shandong University School of Basic Medical Science, Jinan, Shandong, PR China.
4
Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, PR China.
5
Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, PR China. machunhong@sdu.edu.cn.
6
Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, China. machunhong@sdu.edu.cn.

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-1β 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-1β 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-1β 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.

KEYWORDS:

NASH; ROS; Tim-3; macrophage

PMID:
29735977
DOI:
10.1038/s41423-018-0032-0

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