Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity

The metabolic intermediate of acetaminophen(APAP)can cause severe hepatocyte necrosis,which triggers aberrant immune activation of liver non-parenchymal cells(NPC).Overzealous hepatic inflammation determines the morbidity and mortality of APAP-induced liver injury(AILI).Interleukin-1 receptor(IL-1R)signaling has been shown to play a critical role in various inflammatory conditions,but its precise role and underlying mechanism in AILI remain debatable.Herein,we show that NLRP3 inflammasome activation of IL-1βis dispensable to AILI,whereas IL-1α,the other ligand of IL-1R1,accounts for hepatic injury by a lethal dose of APAP.Furthermore,Kupffer cells function as a major source of activated IL-1αin the liver,which is activated by damaged hepatocytes through TLR4/MyD88 signaling.Finally,IL-1αis able to chemoattract and activate CD11b^(+)Gr-1^(+) myeloid cells,mostly neutrophils and inflammatory monocytes,to amplify deteriorated inflammation in the lesion.Therefore,this work identifies that MyD88-dependent activation of IL-1αin Kupffer cells plays a central role in the immunopathogenesis of AILI and implicates that IL-1αis a promising therapeutic target for AILI treatment.