*Purpose: The hepatic proinflammatory response represents a major cause of liver ischemia and reperfusion (IR) injury. Although the role of plasma membrane-bound G protein-coupled bile acid receptor (TGR5) in regulating liver IR injury has been reported, the underlying mechanism remains to be further studied.

*Methods: We analyzed the role and underlying mechanism of TGR5 in regulating macrophage migration and M1/M2 polarization in primary murine macrophage cell cultures, IR-stressed livers of mice and peripheral blood mononuclear cells (PBMCs) from patients post IR stress.

*Results: TGR5 depletion in myeloid cells aggravated liver injury with increased macrophage infiltration and enhanced inflammation in livers post IR. In vitro, TGR5-deficient bone marrow-derived macrophages (BMDMs) displayed increased mobility and enhanced proinflammatory M1 polarization compared to wild type (WT) controls. INT-777, a TGR5 agonist, enhanced the anti-inflammatory effect of TGR5 both in vivo and in vitro. Microarray profiling of WT and TGR5-deficient BMDMs primed with LPS revealed that TGR5-deficient BMDMs exhibited enhanced proinflammatory characteristics. Cathepsin E (Cat E) was the most upregulated gene in TGR5-deficient BMDMs, and 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 PBMCs, correlating with the shift in macrophage M2 polarization. Ursodeoxycholic acid (UDCA) administration enhanced TGR5 activation and the trend of macrophage M2 polarization.

*Conclusions: TGR5 attenuates proinflammatory immune activation by restraining macrophage migration and facilitating macrophage polarization toward the M2 phenotype via suppression of Cat E and thereby protects against liver IR injury.

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