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

Cellular & Molecular Immunology volume 16, pages 878–886 (2019)Cite this article

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.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2016YFE0127000), the National Natural Science Fund for Outstanding Youth Fund (81425012), the National Nature Science Foundation of China (91529305 and 81371831), and the Program for 2016ZDJS07A17.

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Authors and Affiliations

  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

    Xianhong Du, Zhuanchang Wu, Yong Xu, Wen Liu, Tixiao Wang, Fan Yi, Lifen Gao, Xiaohong Liang & Chunhong Ma

  2. Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China

    Yuan Liu

  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

    Chunyang Li

  4. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, PR China

    Cuijuan Zhang

  5. Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, China

    Chunhong Ma

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Du, X., Wu, Z., Xu, Y. et al. Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice. Cell Mol Immunol 16, 878–886 (2019). https://doi.org/10.1038/s41423-018-0032-0

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