Pregnane X Receptor Activation in Liver Macrophages Protects against Endotoxin-Induced Liver Injury

Area of Science:

• Hepatology and Immunology
• Molecular Mechanisms of Disease

Background:

• Endotoxemia causes acute liver injury with high mortality, involving macrophage polarization.
• Pregnane X receptor (PXR) is a nuclear receptor that protects the liver but its role in endotoxemic liver injury is unclear.

Purpose of the Study:

• To investigate the role and mechanism of PXR activation in macrophages during endotoxemic liver injury.

Main Methods:

• Examined PXR expression in human and murine macrophages.
• Activated PXR in macrophages and assessed its effect on liver injury and polarization.
• Used macrophage depletion and PXR knockdown models in mice.
• Investigated PXR interaction with STAT6 signaling in vitro and in vivo.

Main Results:

• PXR activation attenuated endotoxemic liver injury and promoted M2 macrophage polarization.
• Macrophage depletion and PXR knockdown impaired PXR's protective effects.
• PXR activation shifted M1 to M2 polarization in various cell types.
• PXR interacted with STAT6, and blocking either abolished the polarization shift.

Conclusions:

• Macrophage PXR activation mitigates endotoxin-induced liver injury by regulating macrophage polarization via the STAT6 pathway.
• PXR activation in macrophages presents a potential therapeutic strategy for endotoxemic liver injury.