Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*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.
To cite this abstract in AMA style:Zhou H, Zhou S, Wang Q, Rao Z, Wang X, Lu L. TGR5/Cathepsin E Signaling Regulates Macrophage Innate Immune Activation in the Sterile Inflammatory Liver Injury [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/tgr5-cathepsin-e-signaling-regulates-macrophage-innate-immune-activation-in-the-sterile-inflammatory-liver-injury/. Accessed October 26, 2020.
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