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
liver transplantation.
APAP is rapidly taken up from the intestine and metabolized in hepatocytes. A small fraction of the metabolized
APAP forms cytotoxic
mitochondrial protein adducts, leading to hepatocyte
necrosis. The course of disease is not only critically influenced by dose of
APAP and the initial hepatocyte damage, but also by the inflammatory response following
acetaminophen-induced liver injury (AILI). As revealed by mouse models of AILI and corresponding translational studies in ALF patients, necrotic hepatocytes release danger-associated-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 various proinflammatory
cytokines, such as TNF-α or IL-1β, as well as
chemokines (e.g., CCL2) thereby further enhancing
inflammation and increasing the influx of immune cells, like bone-marrow derived monocytes and neutrophils. Monocytes are mainly recruited via their
receptor CCR2 and aggravate
inflammation. Infiltrating monocytes, however, can mature into monocyte-derived macrophages (MoMF), which are, in cooperation with neutrophils, also involved in the resolution of
inflammation. Besides macrophages and neutrophils, distinct lymphocyte populations, especially γδ T cells, are also linked to the inflammatory response following an
APAP overdose. Natural killer (NK), natural killer T (NKT) and T cells possibly further perpetuate
inflammation in AILI. Understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in
disease progression is essential to identify novel therapeutic targets for human disease.