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

Abstract 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‐ sh Car ‐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.