Constitutive Androstane Receptor in Macrophages Regulates Toll‐Like Receptor 4‐Mediated Innate Immune Responses Against Endotoxemic Liver Injury

Macrophage proinflammatory hyperactivation drives the pathogenesis of acute liver injury, a common complication of sepsis. The role of the nuclear receptor constitutive androstane receptor (CAR) in endotoxin-induced liver injury remains unclear. Here, this study reports that CAR is highly expressed in human and murine macrophages. CAR activation markedly attenuated endotoxin-induced liver damage, alleviating hepatocyte death and hepatic inflammation. Macrophage-hepatocyte coculture confirmed that CAR inhibited inflammation through macrophage crosstalk. CAR-mediated hepatoprotection and anti-inflammatory effects are absent in AAV8-F4/80-shCar-treated mice, confirming the essential role of CAR in macrophages. Mechanistically, CAR is found to interact with Tlr4, and the suppressive effects of CAR on TLR4 are proven in Tlr4-/- mice. Furthermore, CAR activation reduced LPS-induced inflammation in hMDMs, BMDMs, RAW264.7, and THP-1 cells, and Car or Tlr4 knockdown abolished CAR-mediated immunosuppression. Overall, these findings showed that macrophage CAR activation attenuated endotoxin-induced liver injury and hepatic inflammation through the TLR4 signaling pathway, providing insights for treating inflammatory liver diseases.