title: Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury.
abstract: 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.
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.forename: Jia
authors.initials: J
authors.lastname: Gu
authors.forename: Zanxian
authors.initials: Z
authors.lastname: Xia
authors.forename: Hongjun
authors.initials: H
authors.lastname: Zhang
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
authors.forename: Richard
authors.initials: R
authors.lastname: Hu
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Han
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005434:Flow Cytometry; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9
keywords: IL-1; TGF-β; hepatic stellate cells; liver injury; matrix metalloproteinase; regulatory T cells; wound healing