Immune mechanisms in acetaminophen-induced acute liver failure

An overdose of acetaminophen (N-acetyl-p-aminophenol, APAP), also termed paracetamol,can cause severe liver damage, ultimately leading to acute liver failure (ALF) with the need of livertransplantation. APAP is rapidly taken up from the intestine and metabolized in hepatocytes. A small fractionof the metabolized APAP forms cytotoxic mitochondrial protein adducts, leading to hepatocyte necrosis. Thecourse of disease is not only critically influenced by dose of APAP and the initial hepatocyte damage, but alsoby the inflammatory response following acetaminophen-induced liver injury (AILI). As revealed by mousemodels of AILI and corresponding translational studies in ALF patients, necrotic hepatocytes release dangerassociated-molecular patterns (DAMPs), which are recognized by resident hepatic macrophages, Kupffer cell(KC), and neutrophils, leading to the activation of these cells. Activated hepatic macrophages release variousproinflammatory cytokines, such as TNF-α or IL-1β, as well as chemokines (e.g., CCL2) thereby furtherenhancing inflammation and increasing the influx of immune cells, like bone-marrow derived monocytesand neutrophils. Monocytes are mainly recruited via their receptor CCR2 and aggravate inflammation.Infiltrating monocytes, however, can mature into monocyte-derived macrophages (MoMF), which are, incooperation with neutrophils, also involved in the resolution of inflammation. Besides macrophages andneutrophils, distinct lymphocyte populations, especially γδ T cells, are also linked to the inflammatoryresponse following an APAP overdose. Natural killer (NK), natural killer T (NKT) and T cells possiblyfurther perpetuate inflammation in AILI. Understanding the complex interplay of immune cell subsets inexperimental models and defining their functional involvement in disease progression is essential to identifynovel therapeutic targets for human disease.