Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury

Ling Lu, Min Feng, Jia Gu, Zanxian Xia, Hongjun Zhang, Sujun Zheng, Zhongping Duan, Richard Hu, Julie Wang, Wei Shi, Cheng Ji, Yi Shen, Guihua Chen, Song Guo Zheng, Yuan Ping Han

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)369-379
Number of pages11
JournalJournal of Molecular Cell Biology
Volume5
Issue number6
DOIs
StatePublished - Dec 1 2013

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Matrix Metalloproteinase 13
Matrix Metalloproteinase 9
Regulatory T-Lymphocytes
Transforming Growth Factor beta
Homeostasis
Wound Healing
Inflammation
Liver
Wounds and Injuries
Matrix Metalloproteinases
Apoptosis
Hepatic Stellate Cells

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Lu, Ling ; Feng, Min ; Gu, Jia ; Xia, Zanxian ; Zhang, Hongjun ; Zheng, Sujun ; Duan, Zhongping ; Hu, Richard ; Wang, Julie ; Shi, Wei ; Ji, Cheng ; Shen, Yi ; Chen, Guihua ; Zheng, Song Guo ; Han, Yuan Ping. / Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury. In: Journal of Molecular Cell Biology. 2013 ; Vol. 5, No. 6. pp. 369-379.
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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.",
author = "Ling Lu and Min Feng and Jia Gu and Zanxian Xia and Hongjun Zhang and Sujun Zheng and Zhongping Duan and Richard Hu and Julie Wang and Wei Shi and Cheng Ji and Yi Shen and Guihua Chen and Zheng, {Song Guo} and Han, {Yuan Ping}",
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Lu, L, Feng, M, Gu, J, Xia, Z, Zhang, H, Zheng, S, Duan, Z, Hu, R, Wang, J, Shi, W, Ji, C, Shen, Y, Chen, G, Zheng, SG & Han, YP 2013, 'Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury', Journal of Molecular Cell Biology, vol. 5, no. 6, pp. 369-379. https://doi.org/10.1093/jmcb/mjt042

Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury. / Lu, Ling; Feng, Min; Gu, Jia; Xia, Zanxian; Zhang, Hongjun; Zheng, Sujun; Duan, Zhongping; Hu, Richard; Wang, Julie; Shi, Wei; Ji, Cheng; Shen, Yi; Chen, Guihua; Zheng, Song Guo; Han, Yuan Ping.

In: Journal of Molecular Cell Biology, Vol. 5, No. 6, 01.12.2013, p. 369-379.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury

AU - Lu, Ling

AU - Feng, Min

AU - Gu, Jia

AU - Xia, Zanxian

AU - Zhang, Hongjun

AU - Zheng, Sujun

AU - Duan, Zhongping

AU - Hu, Richard

AU - Wang, Julie

AU - Shi, Wei

AU - Ji, Cheng

AU - Shen, Yi

AU - Chen, Guihua

AU - Zheng, Song Guo

AU - Han, Yuan Ping

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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.

AB - 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.

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