Macrophage-Derived Protein S Facilitates Apoptotic Polymorphonuclear Cell Clearance by Resolution Phase Macrophages...

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Inflammation resolution requires macrophages to engulf apoptotic cells (efferocytosis) and adopt reparative phenotypes.
• Tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) regulate inflammation and efferocytosis.
• Protein S (PROS1) is a TAM receptor ligand, but its role in inflammation resolution is unclear.

Purpose of the Study:

• To investigate the role of Protein S (PROS1) in macrophage efferocytosis and reprogramming during inflammation resolution.
• To determine if macrophage-derived PROS1 influences the resolution phase of inflammation.

Main Methods:

• Upregulation of Pros1 in macrophages during inflammation resolution was assessed.
• Selective knockout of Pros1 in myeloid cells was performed to evaluate its function.
• Efferocytosis of apoptotic polymorphonuclear cells (PMN) by Pros1-deficient macrophages was measured in vivo and ex vivo.
• Macrophage secretion of inflammatory and anti-inflammatory mediators, as well as pro-resolving enzymes and lipid mediators, was analyzed.

Main Results:

• Pros1 was upregulated in macrophages during inflammation resolution.
• Myeloid-specific knockout of Pros1 impaired efferocytosis of apoptotic PMN.
• Pros1-deficient macrophages exhibited reduced pro-resolving properties, including lower IL-10, arginase-1, 12/15-lipoxygenase, and resolvin D1 production.
• Conversely, Pros1-deficient macrophages secreted higher levels of pro-inflammatory mediators TNFα and CCL3.

Conclusions:

• Macrophage-derived PROS1 is essential for efficient efferocytosis and reprogramming of macrophages towards a pro-resolving phenotype.
• PROS1 plays a critical role in the resolution phase of inflammation.
• PROS1 represents a potential therapeutic target for inflammatory and fibrotic disorders.