Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity

Abstract

Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.

Keywords: Acetaminophen-induced liver injury; Inflammasome; Innate immune response; Macrophages; Monocytes; Neutrophils.

Figure 1:. The sterile inflammatory response to APAP-induced hepatocyte necrosis.

Hepatocyte necrosis after an APAP overdose results in release of DAMPS such as HMGB1 as well as mitochondrial and nuclear DNA fragments. These activate toll like receptors on resident Kupffer cells, which release cytokines and chemokines which then results in transmigration and infiltration of non-primed neutrophils into the necrotic area which facilitates removal of cell debris. Release of cytokines like MCP-1 from Kupffer cells recruits bone marrow derived monocytes, which arrive with a pro-inflammatory phenotype, but mature into a pro-regenerative phenotype once they transmigrate into the milieu surrounding the necrotic cells. These macrophages then facilitate recovery and regeneration of surviving hepatocytes around the necrotic area by activating mitochondrial biogenesis and enhancing hepatocyte division to activate liver recovery after APAP-induced injury.