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

Xiaohui Zhang, Min Feng, Xin Liu, Li Bai, Ming Kong, Yu Chen, Sujun Zheng, Shuang Liu, Yu-Jui Yvonne Wan, Zhongping Duan, Yuan Ping Han

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)67-79
Number of pages13
JournalTranslational Research
Volume169
DOIs
StatePublished - Mar 1 2016

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Tissue Inhibitor of Metalloproteinases
Kupffer Cells
T-cells
Regulatory T-Lymphocytes
Matrix Metalloproteinases
Fibrosis
Liver
Liver Cirrhosis
Matrix Metalloproteinase Inhibitors
Transforming Growth Factors
Immunosuppressive Agents
Lymphocytes
Extracellular Matrix
Hepatocellular Carcinoma
Blood
Tissue
Fibers

ASJC Scopus subject areas

  • Medicine(all)
  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical

Cite this

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. / Zhang, Xiaohui; Feng, Min; Liu, Xin; Bai, Li; Kong, Ming; Chen, Yu; Zheng, Sujun; Liu, Shuang; Wan, Yu-Jui Yvonne; Duan, Zhongping; Han, Yuan Ping.

In: Translational Research, Vol. 169, 01.03.2016, p. 67-79.

Research output: Contribution to journalArticle

Zhang, Xiaohui ; Feng, Min ; Liu, Xin ; Bai, Li ; Kong, Ming ; Chen, Yu ; Zheng, Sujun ; Liu, Shuang ; Wan, Yu-Jui Yvonne ; Duan, Zhongping ; Han, Yuan Ping. / 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. In: Translational Research. 2016 ; Vol. 169. pp. 67-79.
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AU - Liu, Xin

AU - Bai, Li

AU - Kong, Ming

AU - Chen, Yu

AU - Zheng, Sujun

AU - Liu, Shuang

AU - Wan, Yu-Jui Yvonne

AU - Duan, Zhongping

AU - Han, Yuan Ping

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