Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor...

Area of Science:

• Immunology
• Hepatology
• Molecular Biology

Background:

• Acute-phase proteins (APPs) are liver-produced proteins involved in infection and inflammation responses.
• The collective role of APPs in host defense during infections is not well understood.
• gp130 signaling in hepatocytes regulates cytokine responses.

Purpose of the Study:

• To investigate the collective function of APPs during polymicrobial sepsis.
• To determine the role of hepatic gp130 signaling in controlling inflammation and survival during sepsis.
• To elucidate the link between hepatic APPs and myeloid-derived suppressor cells (MDSCs).

Main Methods:

• Used a mouse model with hepatocyte-specific gp130 deletion to abrogate APP production.
• Analyzed mortality, bacterial clearance, systemic inflammation, and STAT3 activation.
• Investigated the role of MDSCs through adoptive transfer experiments.
• Assessed the impact of serum amyloid A and Cxcl1/KC on MDSC function.

Main Results:

• Abrogation of APP production led to increased mortality despite normal bacterial clearance.
• Hepatic gp130-STAT3 signaling was essential for controlling systemic inflammation.
• gp130-STAT3 activation promoted MDSC mobilization, accumulation, and anti-inflammatory function.
• Adoptive transfer of MDSCs rescued gp130-deficient mice from sepsis mortality.
• Specific APPs (serum amyloid A, Cxcl1/KC) were shown to be critical for MDSC regulation.

Conclusions:

• Hepatic gp130-dependent communication via APPs is vital for controlling inflammatory responses during infection.
• APPs orchestrate the function of MDSCs, which are critical for host survival during sepsis.
• Targeting the liver-MDSC axis presents a potential therapeutic strategy for sepsis.