Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG
| Autor: | Xinxin Li, Mianhuan Li, Pingping Luo, George L. Tipoe, Nai-Kei Wong, Hua Wang, Aimin Xu, Kwok-Fai So, Yi Lv, Shuaiyin Chen, Fei Wang, Jia Xiao |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Alcoholic liver disease Alcoholic Liver Disease STAT3 signal transducer and activator of transcription 3 medicine.medical_treatment AST aspartate aminotransferase Catechin Mice 0302 clinical medicine PCR polymerase chain reaction ERK extracellular signal-regulated kinase AMPK adenosine 5′-monophosphate–activated protein kinase HBSS Hanks’ Balanced Salt Solution Medicine Receptor Toll-like Receptor NF-κB nuclear factor kappa B Original Research Liver injury Mice Knockout Toll-like receptor EGCG epigallocatechin-3-gallate TG triglyceride Kupffer cell Gastroenterology MCP-1 monocyte chemotactic protein-1 Interleukin-10 Cytokine medicine.anatomical_structure Editorial Liver iNOS inducible nitric oxide synthase Disease Progression LPS lipopolysaccharide 030211 gastroenterology & hepatology Kupffer Cell TLR Toll-like receptor ALD alcoholic liver disease Kupffer Cells SPR surface plasmon resonance chemical and pharmacologic phenomena Protective Agents 03 medical and health sciences ALT alanine aminotransferase Animals Humans lcsh:RC799-869 Liver Diseases Alcoholic Hepatology Ethanol business.industry MNC mononuclear cell medicine.disease WT wild-type BMT bone marrow transplantation Toll-Like Receptor 2 IL interleukin Toll-Like Receptor 3 TC total cholesterol TLR2 030104 developmental biology Hepatoprotection Cancer research lcsh:Diseases of the digestive system. Gastroenterology NAC N-acetyl-cysteine business EGCG MAPK mitogen-activated protein kinase NAS nonalcoholic fatty liver disease activity score |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 9, Iss 1, Pp 145-160 (2020) |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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