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Article: Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG

TitleDivergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG
Authors
KeywordsAlcoholic Liver Disease
Kupffer Cell
Toll-like Receptor
EGCG
Issue Date2020
PublisherElsevier Inc. The Journal's web site is located at https://www.cmghjournal.org/
Citation
Cellular and Molecular Gastroenterology and Hepatology, 2020, v. 9 n. 1, p. 145-160 How to Cite?
AbstractBackground & Aims: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood. Methods: ALD-associated liver injury were induced in TLR2 knockout (TLR2–/–), TLR3–/–, TLR2–/– bone marrow transplanted (BMT), TLR3–/– BMT, IL-10–/– mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD. Results: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG’s actions. Conclusions: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.
Persistent Identifierhttp://hdl.handle.net/10722/285429
ISSN
2023 Impact Factor: 7.1
2023 SCImago Journal Rankings: 2.702
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLuo, P-
dc.contributor.authorWang, F-
dc.contributor.authorWong, NK-
dc.contributor.authorLv, Y-
dc.contributor.authorLi, X-
dc.contributor.authorLi, M-
dc.contributor.authorTipoe, GL-
dc.contributor.authorSo, KF-
dc.contributor.authorXu, A-
dc.contributor.authorChen, S-
dc.contributor.authorXiao, J-
dc.contributor.authorWang, H-
dc.date.accessioned2020-08-18T03:53:20Z-
dc.date.available2020-08-18T03:53:20Z-
dc.date.issued2020-
dc.identifier.citationCellular and Molecular Gastroenterology and Hepatology, 2020, v. 9 n. 1, p. 145-160-
dc.identifier.issn2352-345X-
dc.identifier.urihttp://hdl.handle.net/10722/285429-
dc.description.abstractBackground & Aims: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood. Methods: ALD-associated liver injury were induced in TLR2 knockout (TLR2–/–), TLR3–/–, TLR2–/– bone marrow transplanted (BMT), TLR3–/– BMT, IL-10–/– mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD. Results: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG’s actions. Conclusions: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.-
dc.languageeng-
dc.publisherElsevier Inc. The Journal's web site is located at https://www.cmghjournal.org/-
dc.relation.ispartofCellular and Molecular Gastroenterology and Hepatology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAlcoholic Liver Disease-
dc.subjectKupffer Cell-
dc.subjectToll-like Receptor-
dc.subjectEGCG-
dc.titleDivergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG-
dc.typeArticle-
dc.identifier.emailTipoe, GL: tgeorge@hku.hk-
dc.identifier.emailSo, KF: hrmaskf@hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.authorityTipoe, GL=rp00371-
dc.identifier.authoritySo, KF=rp00329-
dc.identifier.authorityXu, A=rp00485-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.jcmgh.2019.09.002-
dc.identifier.pmid31562937-
dc.identifier.pmcidPMC6909006-
dc.identifier.scopuseid_2-s2.0-85075560628-
dc.identifier.hkuros312664-
dc.identifier.volume9-
dc.identifier.issue1-
dc.identifier.spage145-
dc.identifier.epage160-
dc.identifier.isiWOS:000503005500009-
dc.publisher.placeUnited States-
dc.identifier.issnl2352-345X-

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