Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background: Although the plasma membrane-bound G protein–coupled bile acid receptor (TGR5) exerts protective roles in various inflammatory diseases, little is known about the effects and underlying mechanisms of TGR5 in regulating innate immune activation during liver IR.
Methods: By genetic and pharmacological disruption of TGR5, we studied whether and how TGR5 regulated macrophage migration and M1/M2 polarization. TGR5 gene induction by ischemia was also analyzed by PCR in human liver tissues.
Results: We found that TGR5 mRNA levels were markedly increased in livers post ischemia from patients undergoing partial hepatoectomy. TGR5 deficiency mice showed greater numbers of macrophage infiltration, leading to enhanced intrahepatic inflammation and ultimately worsen liver IR injury. In contrast, opposite results were found by TGR5 activation with the agonist INT777. In vitro, TGR5 deficiency promoted, and conversely, INT777 inhibited the mobility and M1 phenotype of macrophages. Intracellular signaling pathway analysis revealed that AMP-activated protein kinase (AMPK) was activated, and mammalian target of rapamycin (mTOR) was inhibited by TGR5 knockout in macrophages. Interestingly, the changes of AMPK/mTOR signaling are abrogated by AMPK knockdown in TGR5 deficiency macrophages. Functionally, AMPK knockdown significantly inhibited migration and M1 polarization of TGR5 deficiency macrophages both in vitro and in vivo.
Conclusion: These findings suggest a novel multicomponent TGR5-APMK-mTOR signaling pathway that regulates macrophage innate immune activation during liver ischemia and reperfusion.
CITATION INFORMATION: Zhou S., Zhou H., Liu R., Zhang F., Wang X., Lu L. TGR5-Mediated AMPK/mTOR Signaling Regulates Macrophage Migration and Polarization in Liver Ischemia Reperfusion Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Zhou S, Zhou H, Liu R, Zhang F, Wang X, Lu L. TGR5-Mediated AMPK/mTOR Signaling Regulates Macrophage Migration and Polarization in Liver Ischemia Reperfusion [abstract]. https://atcmeetingabstracts.com/abstract/tgr5-mediated-ampk-mtor-signaling-regulates-macrophage-migration-and-polarization-in-liver-ischemia-reperfusion/. Accessed July 8, 2020.
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