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DOI10.1073/pnas.2020868118
Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22
Wang Q.; Kim S.Y.; Matsushita H.; Wang Z.; Pandyarajan V.; Matsuda M.; Ohashi K.; Tsuchiya T.; Roh Y.S.; Kiani C.; Zhao Y.; Chan M.; Devkota S.; Lu S.C.; Hayashi T.; Carson D.A.; Seki E.
发表日期2021
ISSN00278424
卷号118期号:1
英文摘要Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatlywarranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7-/-mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH. © 2021 National Academy of Sciences. All rights reserved.
英文关键词Alcoholic hepatitis; IL-22; Toll-like receptor
语种英语
scopus关键词1z 1; alcohol; interleukin 22; macrogol; pegylated toll like receptor 7 ligand; peptide derivative; protein Reg3b; protein Reg3g; toll like receptor 7; unclassified drug; alcohol liver disease; animal cell; animal experiment; animal model; animal tissue; antiinflammatory activity; Article; bacterial translocation; Bacteroides; binge drinking; controlled study; disease exacerbation; drug effect; drug efficacy; drug formulation; drug tolerability; fatty liver; female; gene deletion; intestine epithelium; intestine injury; Lactobacillus; liver injury; liver protection; mouse; nonhuman; pathogenesis; priority journal; protein depletion; protein expression; signal transduction; Tlr7 gene; upregulation
来源期刊Proceedings of the National Academy of Sciences of the United States of America
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/181150
作者单位Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States; College of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States; Moores Cancer Center, University of California, San Diego, San Diego, CA 92093, United States
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GB/T 7714
Wang Q.,Kim S.Y.,Matsushita H.,et al. Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22[J],2021,118(1).
APA Wang Q..,Kim S.Y..,Matsushita H..,Wang Z..,Pandyarajan V..,...&Seki E..(2021).Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22.Proceedings of the National Academy of Sciences of the United States of America,118(1).
MLA Wang Q.,et al."Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22".Proceedings of the National Academy of Sciences of the United States of America 118.1(2021).
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