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Int J Biol Sci 2018; 14(9):1033-1040. doi:10.7150/ijbs.25589

Research Paper

Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution

Min Feng1*, Jie Ding1*, Min Wang2, Jie Zhang1,2, Xinhua Zhu1✉, Wenxian Guan1✉

1. Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China;
2. Department of General Surgery, the Affiliated Hospital of Yangzhou University Medical School, Yangzhou 225001, China;
*These authors contributed equally to this work

Abstract

Kupffer cells (KCs) contribute to liver fibrosis resolution by production of a large spectrum of matrix metalloproteinases (MMPs). MMP9 is a major MMP expressed by KCs. However, its role in liver fibrosis resolution remains unclear. In this study, rodent liver fibrosis was induced by intraperitoneal thioacetamide (TAA) and the resolution process was initiated by TAA withdrawal. The role of KC-derived MMP9 in fibrolysis was investigated by adoptive transfer of KCs with or without MMP9 following their depletion. The levels of serum alanine aminotransferase (ALT) and hepatic cytokines were measured during fibrosis regression. The mRNA levels of MMPs and tissue inhibitor of metalloproteinases (TIMPs) were analyzed as well. It was found that removing KCs delayed fibrosis resolution. Adoptive transfer of KCs from WT animals promoted liver fibrosis resolution, compared with transfer of KCs from MMP9-/- mice. Depletion of KCs also resulted in prolonged liver wound healing, which was reversed partially by transferred KCs from either WT or MMP9-/- mice. Likewise, the absence of KCs led to reduction in MMPs mRNA levels and elevation in TIMPs mRNA levels. The expression patterns of MMPs or TIMPs were restored by adoptive transfer of the wild-type but not MMP9-/- KCs. In addition, liver fibrosis resolution was accelerated in MMP9-/- mice by adoptive transferred KCs from WT animals, compared to the KCs from MMP9-/- mice. Overall, KC-derived MMP9 plays a critical role in fibrosis resolution, which might serve as the foundation for developing anti-fibrosis therapy.

Keywords: Kupffer cells, matrix metalloproteinase, fibrosis resolution, liver fibrosis

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How to cite this article:
Feng M, Ding J, Wang M, Zhang J, Zhu X, Guan W. Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution. Int J Biol Sci 2018; 14(9):1033-1040. doi:10.7150/ijbs.25589. Available from http://www.ijbs.com/v14p1033.htm