PMID- 31930324 OWN - NLM STAT- MEDLINE DCOM- 20201214 LR - 20220223 IS - 1460-2377 (Electronic) IS - 0953-8178 (Print) IS - 0953-8178 (Linking) VI - 32 IP - 5 DP - 2020 May 8 TI - Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the beta-catenin destruction complex. PG - 321-334 LID - 10.1093/intimm/dxaa002 [doi] AB - Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5-/-) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5-/- bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5-/- macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5-/- BMDMs. Notably, expression of beta-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3beta to repress the interaction between Gsk3beta and beta-catenin, thus disrupting the beta-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated beta-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5-/- BMDMs. From a therapeutic perspective, TGR5-/- BMDM administration aggravated BDL-induced CHI, which was effectively rescued by beta-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the beta-catenin destruction complex, with therapeutic implications for the management of human CHI. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Society for Immunology. FAU - Rao, Jianhua AU - Rao J AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Yang, Chao AU - Yang C AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Yang, Shikun AU - Yang S AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Lu, Hao AU - Lu H AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Hu, Yuanchang AU - Hu Y AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Lu, Ling AU - Lu L AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Cheng, Feng AU - Cheng F AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Wang, Xuehao AU - Wang X AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Int Immunol JT - International immunology JID - 8916182 RN - 0 (Axin Signaling Complex) RN - 0 (GPBAR1 protein, human) RN - 0 (Lipopolysaccharides) RN - 0 (Receptors, G-Protein-Coupled) SB - IM EIN - Int Immunol. 2022 Jan 1;34(1):53. PMID: 34902019 MH - Animals MH - Axin Signaling Complex/blood/*immunology MH - Bile Ducts/surgery MH - Cholestasis/blood/*immunology/surgery MH - Humans MH - Inflammation/chemically induced/immunology MH - Ligation MH - Lipopolysaccharides/pharmacology MH - Macrophages/drug effects/immunology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Receptors, G-Protein-Coupled/blood/*deficiency/*immunology MH - Signal Transduction PMC - PMC7206975 OTO - NOTNLM OT - CHI OT - Gsk3beta OT - inflammation EDAT- 2020/01/14 06:00 MHDA- 2020/12/15 06:00 PMCR- 2020/01/13 CRDT- 2020/01/14 06:00 PHST- 2019/03/11 00:00 [received] PHST- 2020/01/10 00:00 [accepted] PHST- 2020/01/14 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/01/14 06:00 [entrez] PHST- 2020/01/13 00:00 [pmc-release] AID - 5701402 [pii] AID - dxaa002 [pii] AID - 10.1093/intimm/dxaa002 [doi] PST - ppublish SO - Int Immunol. 2020 May 8;32(5):321-334. doi: 10.1093/intimm/dxaa002.