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

ABSTRACT: BACKGROUND & 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.

SUBMITTER: Luo P 

PROVIDER: S-EPMC6909006 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature