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.