Fig. 1
Immunologic mechanisms of AILI. Overdose APAP is metabolized by cytochrome P450 to generate the highly reactive metabolite NAPQI. Excessive NAPQI depletes GSH, leading to formation of protein adducts and acute liver injury. Necrotic hepatocytes release DAMPs that drive hepatic infiltration of immune cells. Activated immune cells secrete various cytokines and chemokines, including pro-inflammatory mediators and anti-inflammatory mediators, to modulate the balance between liver damage and liver repair and regeneration. During APAP challenge: (1) Hepatic DCs prevent NK cells activation and attract neutrophils apoptosis. (2) KCs release pro-inflammatory mediators to recruit neutrophils and attract MoMF. (3) Neutrophils release ROS to trigger the transformation of pro- inflammatory Ly6ChiCX3CR1lo monocytes/macrophages skewing toward reparative Ly6CloCX3CR1hi macrophages. (4) IL- 33, selectively released by LSECs, stimulates eosinophils to secrete IL-4, which promotes macrophages to produce a plethora of eotaxin-2 (CCL24) to trigger the recruitment of eosinophils. In addition, activated B cells produce antibodies participating in AILI. CYP450 cytochrome P450, NAPQI N-acetyl-p-benzoquinone imine, GSH glutathione, APAP-ADs acetaminophen protein adducts, DAMPs damage-associated molecular patterns, NK cells natural killer cells, NKT cells natural killer T cells, DCs dendritic cells, MoMF monocyte-derived macrophages, LSECs liver sinusoidal endothelial cells,TNF-α tumor necrosis factor-α, IL-1βinterleukin-1β, ROS reactive oxygen species, RNS reactive nitrogen species, IFN-γ interferon-γ, OPN osteopontin, CXCL1 C-X-C Motif Chemokine Ligand 1, NE neutrophil elastase, MHC-II major histocompatibility complex-II,TLRs Toll-like receptors, TGF-β transforming growth factor-β