Thioredoxin reductase 1 regulates hepatic inflammation and macrophage activation during acute cholestatic liver injury.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 01 2023
01 01 2023
Historique:
received:
25
07
2022
accepted:
27
10
2022
entrez:
12
1
2023
pubmed:
13
1
2023
medline:
17
1
2023
Statut:
epublish
Résumé
Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by periportal inflammation with progression to hepatic fibrosis and ultimately cirrhosis. We recently reported that the thioredoxin antioxidant response is dysregulated during primary sclerosing cholangitis. The objective of this study was to examine the impact of genetic and pharmacological targeting of thioredoxin reductase 1 (TrxR1) on hepatic inflammation and liver injury during acute cholestatic injury. Primary mouse hepatocytes and intrahepatic macrophages were isolated from 3-day bile duct ligated (BDL) mice and controls. Using wildtype and mice with a liver-specific deletion of TrxR1 (TrxR1LKO), we analyzed the effect of inhibition or ablation of TrxR1 signaling on liver injury and inflammation. Immunohistochemical analysis of livers from BDL mice and human cholestatic patients revealed increased TrxR1 staining in periportal macrophages and hepatocytes surrounding fibrosis. qPCR analysis of primary hepatocytes and intrahepatic macrophages revealed increased TrxR1 mRNA expression following BDL. Compared with sham controls, BDL mice exhibited increased inflammation, necrosis, and increased mRNA expression of pro-inflammatory cytokines, fibrogenesis, the NLRP3 inflammatory complex, and increased activation of NFkB, all of which were ameliorated in TrxR1LKO mice. Importantly, following BDL, TrxR1LKO induced periportal hepatocyte expression of Nrf2-dependent antioxidant proteins and increased mRNA expression of basolateral bile acid transporters with reduced expression of bile acid synthesis genes. In the acute BDL model, the TrxR1 inhibitor auranofin (10 mg/kg/1 d preincubation, 3 d BDL) ameliorated BDL-dependent increases in Nlrp3, GsdmD, Il1β, and TNFα mRNA expression despite increasing serum alanine aminotransferase, aspartate aminotransferase, bile acids, and bilirubin. These data implicate TrxR1-signaling as an important regulator of inflammation and bile acid homeostasis in cholestatic liver injury.
Sections du résumé
BACKGROUND AND AIMS
Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by periportal inflammation with progression to hepatic fibrosis and ultimately cirrhosis. We recently reported that the thioredoxin antioxidant response is dysregulated during primary sclerosing cholangitis. The objective of this study was to examine the impact of genetic and pharmacological targeting of thioredoxin reductase 1 (TrxR1) on hepatic inflammation and liver injury during acute cholestatic injury.
APPROACH AND RESULTS
Primary mouse hepatocytes and intrahepatic macrophages were isolated from 3-day bile duct ligated (BDL) mice and controls. Using wildtype and mice with a liver-specific deletion of TrxR1 (TrxR1LKO), we analyzed the effect of inhibition or ablation of TrxR1 signaling on liver injury and inflammation. Immunohistochemical analysis of livers from BDL mice and human cholestatic patients revealed increased TrxR1 staining in periportal macrophages and hepatocytes surrounding fibrosis. qPCR analysis of primary hepatocytes and intrahepatic macrophages revealed increased TrxR1 mRNA expression following BDL. Compared with sham controls, BDL mice exhibited increased inflammation, necrosis, and increased mRNA expression of pro-inflammatory cytokines, fibrogenesis, the NLRP3 inflammatory complex, and increased activation of NFkB, all of which were ameliorated in TrxR1LKO mice. Importantly, following BDL, TrxR1LKO induced periportal hepatocyte expression of Nrf2-dependent antioxidant proteins and increased mRNA expression of basolateral bile acid transporters with reduced expression of bile acid synthesis genes. In the acute BDL model, the TrxR1 inhibitor auranofin (10 mg/kg/1 d preincubation, 3 d BDL) ameliorated BDL-dependent increases in Nlrp3, GsdmD, Il1β, and TNFα mRNA expression despite increasing serum alanine aminotransferase, aspartate aminotransferase, bile acids, and bilirubin.
CONCLUSIONS
These data implicate TrxR1-signaling as an important regulator of inflammation and bile acid homeostasis in cholestatic liver injury.
Identifiants
pubmed: 36633484
doi: 10.1097/HC9.0000000000000020
pii: 02009842-202301010-00013
pmc: PMC9833450
doi:
Substances chimiques
Antioxidants
0
Bile Acids and Salts
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
RNA, Messenger
0
Thioredoxin Reductase 1
EC 1.8.1.9
TXNRD1 protein, human
EC 1.8.1.9
Txnrd1 protein, mouse
EC 1.8.1.9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0020Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK048520
Pays : United States
Organisme : NIH HHS
ID : R21 OD026444
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK123738
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG055022
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002535
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Références
Cell Mol Gastroenterol Hepatol. 2020;9(4):679-688
pubmed: 31887435
Am J Physiol Gastrointest Liver Physiol. 2019 Dec 1;317(6):G773-G783
pubmed: 31604030
Free Radic Biol Med. 2012 Feb 1;52(3):671-682
pubmed: 22155056
J Biol Chem. 2005 May 6;280(18):17707-14
pubmed: 15750181
Redox Biol. 2022 Jul 14;55:102404
pubmed: 35868156
Int J Mol Sci. 2018 Oct 01;19(10):
pubmed: 30275402
Free Radic Biol Med. 2019 Nov 1;143:101-114
pubmed: 31377417
Hepatology. 2012 Feb;55(2):553-62
pubmed: 21953613
J Biol Chem. 2005 Oct 14;280(41):34538-47
pubmed: 16105840
Am J Physiol Gastrointest Liver Physiol. 2008 Feb;294(2):G506-19
pubmed: 18096608
Diabetes Obes Metab. 2010 Oct;12 Suppl 2:116-25
pubmed: 21029308
Biochem Biophys Res Commun. 2009 Nov 20;389(3):431-6
pubmed: 19732748
Biochim Biophys Acta. 2014 Oct;1840(10):3153-61
pubmed: 25065288
Xenobiotica. 2021 May;51(5):605-615
pubmed: 33522359
Nat Commun. 2018 Apr 11;9(1):1393
pubmed: 29643332
Sci Transl Med. 2013 Oct 9;5(206):206ra137
pubmed: 24107776
Antioxidants (Basel). 2021 Apr 21;10(5):
pubmed: 33919055
Cell Cycle. 2016;15(4):559-72
pubmed: 26743692
Toxicol Appl Pharmacol. 2008 Jan 1;226(1):74-83
pubmed: 17935745
Oncotarget. 2016 Dec 20;7(51):83951-83963
pubmed: 27924062
Mol Med Rep. 2019 Jan;19(1):3-14
pubmed: 30483776
Elife. 2020 Feb 25;9:
pubmed: 32096759
Exp Mol Pathol. 2018 Feb;104(1):1-8
pubmed: 29180269
PLoS One. 2009 Jul 07;4(7):e6158
pubmed: 19584930
J Hepatol. 2014 Jan;60(1):160-6
pubmed: 23978715
Am J Transplant. 2018 Jan;18 Suppl 1:172-253
pubmed: 29292603
Free Radic Biol Med. 2007 Sep 15;43(6):911-23
pubmed: 17697936
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
Cell Stress Chaperones. 2006 Winter;11(4):356-63
pubmed: 17278884
Front Cell Dev Biol. 2022 Feb 10;10:826204
pubmed: 35223849
Antioxidants (Basel). 2020 Oct 23;9(11):
pubmed: 33114221
Hepatol Commun. 2019 Sep 27;3(12):1674-1686
pubmed: 31832574
Antioxid Redox Signal. 2012 Nov 15;17(10):1407-16
pubmed: 22607006
Biochim Biophys Acta. 2009 Jun;1790(6):495-526
pubmed: 19364476
Antioxid Redox Signal. 2015 Oct 1;23(10):823-53
pubmed: 26058897
Am J Pathol. 2011 Jan;178(1):175-86
pubmed: 21224055
JPEN J Parenter Enteral Nutr. 2022 Jul;46(5):1096-1106
pubmed: 34664730
Front Immunol. 2018 Sep 25;9:2201
pubmed: 30319645
Int Immunopharmacol. 2019 May;70:147-155
pubmed: 30802677
Commun Biol. 2021 Jun 30;4(1):824
pubmed: 34193972
Hepatology. 2019 Feb;69(2):473-475
pubmed: 30251326
Exp Mol Pathol. 2018 Aug;105(1):32-36
pubmed: 29852184
Hepatology. 2021 May;73(5):1836-1854
pubmed: 32748971
J Hepatol. 2018 Sep;69(3):676-686
pubmed: 29802947
Hepatology. 2003 Aug;38(2):374-84
pubmed: 12883481
J Cell Sci. 2010 Jul 15;123(Pt 14):2402-12
pubmed: 20571049
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11408-11417
pubmed: 31097586
Cell Rep. 2017 Jun 27;19(13):2771-2781
pubmed: 28658624
J Hepatol. 2017 Sep;67(3):549-558
pubmed: 28529147
Am J Pathol. 2016 Sep;186(9):2238-47
pubmed: 27452297