Fpr2(−/−) Mice Developed Exacerbated Alcohol-Associated Liver Disease

SIMPLE SUMMARY: Alcohol-associated liver disease (ALD) is a global healthcare problem, and the mechanisms of ALD development are not fully understood. In this study, we found that loss of formyl peptide receptor 2 (FPR2) worsened alcohol-induced injury and inflammation and altered liver regeneration. An exacerbation of ALD due to FPR2 gene knockout was associated with abnormal immune responses. This study demonstrated that FPR2 plays an important role in the pathogenesis of ALD. ABSTRACT: Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate the role of formyl peptide receptor 2 (FPR2), a receptor for immunomodulatory signals, in the pathogenesis of ALD. WT and Fpr2(−/−) mice were exposed to chronic–binge ethanol administration and subsequently assessed for liver injury, inflammation, and markers of regeneration. The differentiation capacity of liver macrophages and the oxidative burst activity of neutrophils were also examined. Compared to WT, Fpr2(−/−) mice developed more severe liver injury and inflammation and had compromised liver regeneration in response to ethanol administration. Fpr2(−/−) mice had fewer hepatic monocyte-derived restorative macrophages, and neutrophils isolated from Fpr2(−/−) mice had diminished oxidative burst capacity. Fpr2(−/−) MoMF differentiation was restored when co-cultured with WT neutrophils. Loss of FPR2 led to exacerbated liver damage via multiple mechanisms, including abnormal immune responses, indicating the crucial role of FPR2 in ALD pathogenesis.