Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22

Significance Alcoholic hepatitis (AH) is a severe form of alcohol-associated liver disease (ALD) that is characterized by chronic liver injury and inflammation. The current treatment strategy for AH involves the use of corticosteroids, despite a lack of evidence supporting their efficacy, because other effective therapeutic agents are not available. Here, we demonstrate that activation of TLR7 signaling via the oral administration of 1Z1, which is a synthetic TLR7 ligand that does not elicit systemic side effects, protects against liver injury in an AH mouse model. The therapeutic effect of 1Z1 requires TLR7 expression and is mediated by intestinal IL-22 upregulation. Our study suggests that 1Z1-induced TLR7 activation and IL-22 induction may be a therapeutic approach for the treatment of AH. Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. 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.