Hippocampal NLRP3 Inflammasome Drives Anxiety- and Depressive-Like Behaviors Following Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) is a considerable and potentially severe adverse reaction to medications. As drug abuse continues to rise, managing drug-induced liver toxicity has become a considerable challenge for clinicians. Depression is a chronic neurological disorder with a rising incidence globally in recent years, adding to the overall societal burden. Numerous clinical studies have suggested a link between DILI and mental illnesses, with inflammation potentially playing a mediating role. However, the exact mechanisms remain unclear. Here, we established a mouse model of DILI through acetaminophen (APAP) exposure and assessed the correlation between mental disorder and NLRP3 inflammasome. We found that DILI mice exhibited anxiety- and depressive-like behaviors, along with disrupted blood-brain barrier integrity and a significant increase in hippocampal NLRP3 inflammasome levels. Nlrp3 knockout or hippocampal Nlrp3 knockdown ameliorated DILI-induced anxiety- and depressive-like behaviors. Moreover, N-acetylcysteine, an agent against APAP-induced hepatotoxicity, inhibited NLRP3 inflammasome activation and alleviated anxiety- and depressive-like behaviors in DILI mice. These results indicate that the NLRP3 inflammasome might be a promising target for the treatment of patients with DILI who experience comorbid anxiety and depression.