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Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury Free
Ling Lu1,†, Min Feng2,†, Jia Gu1, Zanxian Xia3, Hongjun Zhang4, Sujun Zheng5, Zhongping Duan5, Richard Hu6, Julie Wang4, Wei Shi4, Cheng Ji4, Yi Shen7, Guihua Chen8, Song Guo Zheng7,9,*, and Yuan-Ping Han10,*
1Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
2Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
3School of Biological Sciences and Technology, Central South University, Changsha 410013, China
4Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
5Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
6Olive View-UCLA Medical Center, Los Angeles, CA 91342, USA
7Penn State University Hershey College of Medicine, Hershey, PA 17033, USA
8Department of Liver Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
9Tongji University Shanghai East Hospital, Institute of Immunology, Shanghai 200120, China
10The Center for Growth, Metabolism and Aging, the Key Laboratory for Bio-Resource and Eco-Environment, and the National Key Laboratory of Biotherapy, Sichuan University, Chengdu 610064, China *Correspondence to:Yuan-Ping Han, E-mail: hanyp@scu.edu.cn; Song Guo Zheng, E-mail: szheng1@hmc.psu.edu
J Mol Cell Biol, Volume 5, Issue 6, December 2013, 369-379,  https://doi.org/10.1093/jmcb/mjt042
Keyword: liver injury, wound healing, regulatory T cells, TGF-β, IL-1, hepatic stellate cells, matrix metalloproteinase

During the acute liver injury, immune responses are provoked into eliciting inflammation in the acute phase. In the healing phase, the inflammation is terminated for wound healing and restoration of immune homeostasis. In this study, we sought to address how regulatory T cells (Tregs) are involved in the progression of liver injury and repair. In the acute phase, intrahepatic Tregs (CD4+FoxP3+Helios+) diminished promptly through apoptosis, which was followed by inflammation and tissue injury. In the healing phase, a new subset of Tregs (CD4+Foxp3+Helios−) was generated in correlation with the matrix metalloproteinase (MMP) cascade and transforming growth factor-beta (TGF-β) activation that were manifested mainly by hepatic stellate cells. Moreover, the induction of induced Tregs and wound healing were both impaired in mice lacking TGF-β signaling or MMPs. The depletion of induced Tregs also impeded wound healing for tissue repair. Together, this study demonstrates the mechanism that the loss of nTregs through apoptosis in the acute phase may facilitate inflammation, while regenerated Tregs through MMP9/13-dependent activation of TGF-β in the healing phase are critical to terminate inflammation and allow for wound healing.


Volume 5, Issue 6
December 2013