TGR5/Cathepsin E signaling regulates macrophage innate immune activation in liver ischemia and reperfusion injury
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Updated: Aug 14, 2026
Long Term Intravital Multiphoton Microscopy Imaging of Immune Cells in Healthy and Diseased Liver Using CXCR6.Gfp Reporter Mice
Published on: March 24, 2015
Haoming Zhou1, Shun Zhou1, Yong Shi1
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Donor Liver Transplantation, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing, China.
Abstract:
The role and underlying mechanism of plasma membrane-bound G protein-coupled bile acid receptor (TGR5) in regulating macrophage innate immune activation during liver ischemia and reperfusion (IR) injury remains largely unclear. Here, we demonstrated that TGR5 depletion in myeloid cells aggravated liver injury with increased macrophage infiltration and enhanced inflammation in livers post-IR. While TGR5 deficiency enhanced mobility and proinflammatory M1 polarization of macrophages, TGR5 agonist enhanced the anti-inflammatory effect of TGR5 both in vivo and in vitro. Microarray profiling revealed that TGR5-deficient macrophages exhibited enhanced proinflammatory characteristics and cathepsin E (Cat E) was the most upregulated gene. Knockdown of Cat E abolished the enhanced mobility and shift of macrophage phenotypes induced by TGR5 depletion. Moreover, Cat E knockdown attenuated liver IR injury and liver inflammation in myeloid TGR5-deficient mice. In patients undergoing partial hepatectomy, IR stress promoted TGR5 activation of CD11b+ cells in peripheral blood mononuclear cells, correlating with the shift in macrophage M2 polarization. Ursodeoxycholic acid administration enhanced TGR5 activation and the trend in macrophage M2 polarization. Our results suggest that TGR5 attenuates proinflammatory immune activation by restraining macrophage migration and facilitating macrophage M2 polarization via suppression of Cat E and thereby protects against liver IR injury.
Insights
The G protein-coupled bile acid receptor (TGR5) protects the liver from ischemia-reperfusion injury by reducing inflammation. TGR5 activation suppresses macrophage migration and promotes anti-inflammatory M2 polarization via cathepsin E inhibition.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Liver ischemia-reperfusion (IR) injury is a significant clinical challenge.
- The role of the bile acid receptor TGR5 in macrophage-mediated liver IR injury is not well understood.
Purpose of the Study:
- To elucidate the mechanism by which TGR5 regulates macrophage innate immune activation in liver IR injury.
- To investigate the therapeutic potential of TGR5 agonists in mitigating liver IR injury.
Main Methods:
- Utilized myeloid-specific TGR5-deficient mice and TGR5 agonists for in vivo and in vitro studies.
- Performed microarray profiling to identify key molecular players.
- Investigated the role of cathepsin E (Cat E) in TGR5-mediated macrophage regulation.
- Analyzed patient samples from partial hepatectomy to correlate TGR5 activation with macrophage polarization.
Main Results:
- TGR5 depletion exacerbated liver IR injury, increasing macrophage infiltration and inflammation.
- TGR5 deficiency enhanced macrophage mobility and M1 polarization, partly via upregulation of Cat E.
- Cat E knockdown ameliorated liver injury and inflammation in TGR5-deficient mice.
- TGR5 activation in patients correlated with M2 macrophage polarization and was enhanced by ursodeoxycholic acid.
Conclusions:
- TGR5 activation attenuates liver IR injury by suppressing proinflammatory macrophage activation.
- TGR5 restrains macrophage migration and promotes M2 polarization through Cat E suppression.
- Targeting TGR5 represents a potential therapeutic strategy for liver IR injury.
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