Mesencephalic astrocyte-derived neurotrophic factor reprograms macrophages to ameliorate acetaminophen-induced acute liver injury via p38 MAPK pathway

Acetaminophen (APAP)-induced liver injury (AILI) is the most frequent cause of acute liver failure; but the underlying mechanisms still remain obscure. Macrophages and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of AILI. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified 18-kDa soluble protein, whose expression and secretion are stimulated by ER stress. To investigate the role of myeloid cell MANF in the pathogenesis of AILI, we assayed serum and liver samples from AILI model mice and patients with drug-induced liver injury (DILI). We demonstrated that the levels of MANF were elevated in patients with DILI and in mice with AILI. Moreover, myeloid-specific MANF knockout mice were generated and used. It was observed that a delayed liver recovery from myeloid-specific MANF gene knockout mice following APAP overdose compared to that from wild-type mice. MANF deficiency in myeloid cells resulted in increased infiltrating monocyte-derived macrophages (MoMFs) but reduced restorative Ly6C low macrophages after APAP treatment. MANF supplementation increased restorative Ly6C low macrophages and subsequently alleviated liver injury. Moreover, MANF could enhance IL-10 expression and phagocytosis in macrophages via p38 MAPK pathway. Altogether, MANF seems to be a critical immune modulator in promoting liver repair via reducing and reprogramming MoMFs. MANF perhaps promoted the phenotype conversion of pro-inflammatory MoMFs to pro-restorative Ly6C low MoMFs via p38 MAPK pathway, particularly through enhancing IL-10 and phagocytosis.