Good Cells Go Bad: Immune Dysregulation in the Transition from Acute Liver Injury to Liver Failure After Acetaminophen Overdose

Abstract

The role of inflammatory cells and other components of the immune system in acetaminophen (APAP)-induced liver injury and repair has been extensively investigated. Although this has resulted in a wealth of information regarding the function and regulation of immune cells in the liver after injury, apparent contradictions have fueled controversy around the central question of whether the immune system is beneficial or detrimental after APAP overdose. Ultimately, this may not be a simple assignment of "good" or "bad." Clinical studies have clearly demonstrated an association between immune dysregulation and a poor outcome in patients with severe liver damage/liver failure induced by APAP overdose. To date, studies in mice have not uniformly replicated this connection. The apparent disconnect between clinical and experimental studies has perhaps stymied progress and further complicated investigation of the immune system in APAP-induced liver injury. Mouse models are often dismissed as not recapitulating the clinical scenario. Moreover, clinical investigation is most often focused on the most severe APAP overdose patients, those with liver failure. Notably, recent studies have made it apparent that the functional role of the immune system in the pathogenesis of APAP-induced liver injury is highly context dependent and greatly influenced by the experimental conditions. In this review, we highlight some of these recent findings and suggest strategies seeking to resolve and build on existing disconnects in the literature. SIGNIFICANCE STATEMENT: Acetaminophen overdose is the most frequent cause of acute liver failure in the United States. Studies indicate that dysregulated innate immunity contributes to the transition from acute liver injury to acute liver failure. In this review, we discuss the evidence for this and the potential underlying causes.

Fig. 1.

Pathogenesis of APAP-induced acute liver injury and ALF. APAP-induced liver injury in mice and patients triggers a rapid inflammatory response. A tightly regulated balance between inflammatory and repair pathways facilitates the resolution of injury and the restoration of liver function, resulting in a full recovery. In a subset of patients and in mice treated with a high dose of APAP, acute liver injury produces an exaggerated inflammatory response, leading to SIRS. This condition contributes to the development of multiorgan dysfunction syndrome (MODS) and hepatic encephalopathy, a feature of ALF. To counter the hyperactive immune response, high levels of anti-inflammatory mediators are produced, leading to CARS. This immunosuppressive condition increases susceptibility to infections and disrupts immune mediated repair pathways. Created with Biorender.com.