PPARα agonist ameliorates cholestatic liver injury by regulating hepatic macrophage homeostasis

Inflammatory response plays an essential role in the pathogenesis of cholestatic liver injury. PPARα agonists have been shown to regulate bile acid homeostasis and hepatic inflammation. However, the immunoregulatory mechanisms through which PPARα agonists ameliorate cholestatic liver injury remain unclear. In this study, surgical bile duct ligation was performed to establish a mouse model of cholestasis. Our study revealed that PPARα agonist alleviated cholestatic liver injury in mice by suppressing inflammatory response, reducing neutrophil infiltration, and promoting M2-like macrophage polarization. CyTOF analysis showed that PPARα agonist increased the proportion of anti-inflammatory F4/80^hiCD44⁺MHCII^- M2-like macrophages while decreasing the proportion of pro-inflammatory CD64⁺CX3CR1⁺CCR2^hiVISTA^hiCD172a⁺CD44^hi M1-like MoMFs. Additionally, scRNA-seq indicated that PPARα agonist regulated the developmental trajectory and homeostasis of hepatic macrophages. Mechanistically, PPARα agonist may influence the expression of immune regulators in heterogeneous macrophages to exert protective effects against cholestasis. In addition, the CCL and MIF signaling pathways may participate in the communication among hepatic immune cells, including macrophages, neutrophils, natural killer cells, and dendritic cells, in response to the PPARα agonist. In conclusions, PPARα agonist alleviated cholestatic liver injury by attenuating the inflammatory response and restoring hepatic macrophage homeostasis. This study might enhance the understanding of the immunoregulatory mechanisms of PPARα agonists, providing promising therapeutic targets for cholestatic liver diseases.