Progranulin drives acetaminophen-induced acute liver injury by limiting hepatic recruitment of eosinophils via suppressing interleukin-33 expression

Drug-induced liver injury (DILI), particularly acetaminophen (APAP)-induced acute liver injury (ALI), is the leading cause of acute liver failure. Progranulin (PGRN) is a multifunctional glycoprotein. However, the role of PGRN in APAP-induced ALI remains unknown. Here, we found that PGRN serum concentration increased and correlated with disease severity in the patients with APAP overdose. Mice with PGRN deficiency were protected from APAP-induced ALI or concanavalin A (ConA)-induced ALI. They exhibited substantially increased hepatic recruitment of eosinophils, which depended on up-regulated IL-33 that was primarily released from liver sinusoidal endothelial cells (LSECs). Moreover, treatment of mice with blocking PGRN antibody could prophylactically and therapeutically treat APAP- or ConA-induced ALI, while injection of recombinant PGRN protein enhanced APAP-induced liver damage and worsened survival. Mechanistically, PGRN inhibited APAP-induced IL-33 expression in LSECs by dampening the activation of AMP-activated protein kinase (AMPK)-forkhead box O3 (FOXO3) signaling pathway. Therefore, PGRN should be considered as a new biomarker and potential therapeutic target to treat DILI.