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

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• 作者：Xiaohui Zhang^a ; Min Feng^b ; Xin Liu^a ; Li Bai^a ; Ming Kong^a ; Yu Chen^a ; Sujun Zheng^a ; Shuang Liu^a ; Yu-Jui Yvonne Wan^c ; Zhongping Duan^a ; ^{duan2517@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yuan-Ping Han^d ; ^{hanyp@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：α-SMA ; α-smooth muscle actin ; CCl4 ; carbon tetrachloride ; CTL ; cytotoxic lymphocyte ; CTLA-4 ; cytotoxic T-lymphocyte&ndash ; associated protein 4 ; DMEM ; Dulbecco modified Eagle medium ; ECM ; extracellular matrix ; FACS ; fluorescence activated cell sorting ; GITR ; glucocorticoid-induced TNF receptor ; HCC ; hepatocellular carcinoma ; HSCs ; hepatic stellate cells ; KCs ; Kupffer cells ; LPS ; lipopolysaccharide ; MMP ; matrix metalloproteinase ; MNCs ; mononuclear cells ; PBS ; phosphate buffered saline ; PSC ; primar
• 刊名：Translational Research
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：169
• 期：Complete
• 页码：67-79.e2
• 全文大小：2441 K

文摘

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.