RXRα suppression drives hepatic metabolic and immune dysfunction in sepsis

Area of Science:

• Immunology
• Hepatology
• Molecular Biology

Background:

• Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to organ dysfunction and failure.
• The liver plays a critical role in host defense and metabolic regulation during sepsis.
• Identifying molecular targets that enhance host resilience is crucial for improving sepsis outcomes.

Purpose of the Study:

• To investigate the role of hepatocyte retinoid X receptor alpha (RXRα) in host resilience during polymicrobial sepsis.
• To determine the regulatory mechanisms of RXRα in the septic liver.
• To evaluate the therapeutic potential of RXRα activation in sepsis.

Main Methods:

• Utilized polymicrobial sepsis models in mice.
• Investigated the transcriptional regulation of RXRα by hepatocyte nuclear factor 4α (HNF4α).
• Performed transcriptomic analyses to assess liver response to RXRα activation with bexarotene.
• Generated hepatocyte-specific inducible RXRα-deficient mice.
• Examined the impact of RXRα deficiency on Kupffer cell populations and bacterial dissemination.

Main Results:

• Sepsis rapidly decreases hepatic RXRα mRNA and protein levels.
• The septic liver exhibits partial resistance to pharmacological RXRα activation.
• Prophylactic, but not therapeutic, administration of bexarotene improves survival, preserves metabolic stability, and enhances bacterial clearance.
• Protection conferred by bexarotene is dependent on hepatocyte RXRα.
• Loss of RXRα in hepatocytes leads to reduced Kupffer cell numbers, increased bacterial dissemination, and mortality.
• RXRα maintains the hepatic macrophage niche, linking hepatocellular function to systemic antibacterial defense.

Conclusions:

• Hepatocyte RXRα is a key integrator of host resilience during sepsis.
• Targeting hepatic RXRα, particularly prophylactically, represents a potential therapeutic strategy for sepsis.
• RXRα's role in maintaining the hepatic macrophage niche is critical for effective bacterial clearance and host survival.