title: Persistence of cirrhosis is maintained by intrahepatic regulatory T cells that inhibit fibrosis resolution by regulating the balance of tissue inhibitors of metalloproteinases and matrix metalloproteinases.
abstract: Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with cirrhosis or hepatocellular carcinoma. The role of Tregs in the progression of liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of liver fibrosis. As a consequence of Tregs depletion, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with fibrosis resolution. Kupffer cells (KCs) are the main source of MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit MMP expression of KCs even at a low ratio; and anti-transforming growth factor-β (TGF-β) significantly reversed the inhibition of Tregs on MMP. Meanwhile, we also found that after Tregs depletion, TGF-β levels decreased in the mice liver, unlike in fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the MMP/TIMP balance and that the suppression of KC-mediated MMP expression contributed to the regulatory process.
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Liver Transplantation, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Kong
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, Calif.
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
authors.affiliation: Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China. Electronic address: duan2517@163.com.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
authors.affiliation: The Center for Growth, Metabolism and Aging, The Key Laboratory for Bio-Resource and Eco-Environment, College of Life Science, and The National Key Laboratory of Biotherapy, Sichuan University, Chengdu, China. Electronic address: hanyp@scu.edu.cn.
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Han
mesh_terms: D000818:Animals; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000276:immunology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases