FAM96A knock-out promotes alternative macrophage polarization and protects mice against sepsis

Area of Science:

• Immunology
• Molecular Biology
• Pathophysiology

Background:

• Sepsis is a life-threatening condition with high mortality and limited treatment options.
• Family with sequence similarity 96 member A (FAM96A) is a conserved protein with poorly understood immune functions.
• Understanding novel regulators of the immune response is crucial for developing effective sepsis therapies.

Purpose of the Study:

• To investigate the role of FAM96A in the immune response during sepsis.
• To identify the specific immune cells and mechanisms through which FAM96A influences sepsis progression.
• To explore FAM96A as a potential therapeutic target for sepsis.

Main Methods:

• Utilized Fam96a knockout (Fam96a-/-) mice in sepsis models (cecal ligation and puncture, endotoxemia).
• Assessed organ damage, survival rates, bacterial clearance, and cytokine levels.
• Investigated immune cell subsets, including macrophages, using in vivo depletion and adoptive transfer experiments.
• Performed bone marrow-derived macrophage (BMDM) polarization assays and analyzed immunometabolism (ROS, glucose uptake).

Main Results:

• Fam96a-/- mice exhibited significantly enhanced resistance to sepsis, characterized by reduced organ damage, increased survival, and improved bacterial clearance.
• FAM96A deficiency led to decreased levels of pro-inflammatory cytokines.
• Macrophages were identified as key cell types mediating FAM96A's protective effects in sepsis.
• FAM96A deficiency promoted M2 macrophage polarization and altered macrophage immunometabolism from oxidative phosphorylation to glycolysis.

Conclusions:

• FAM96A plays a critical role in regulating the inflammatory response during sepsis.
• Targeting FAM96A may offer a novel therapeutic strategy for sepsis by modulating macrophage function and immunometabolism.
• This study provides new genomic insights into sepsis pathogenesis and treatment.