Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates...

Area of Science:

• Immunology
• Vascular Biology
• Complement System Biology

Background:

• Complement factor H (CFH) is a key regulator of complement component 3 (C3) consumption, preventing excessive complement activation.
• Genetic variations in CFH are linked to predisposition to chronic inflammatory diseases.
• The role of CFH in atherosclerosis, a chronic inflammatory vascular disease, remains incompletely understood.

Purpose of the Study:

• To investigate the impact of CFH on the development and progression of atherosclerosis.
• To elucidate the specific mechanisms by which CFH influences macrophage function and inflammatory processes within atherosclerotic plaques.

Main Methods:

• Utilized a mouse model of atherosclerosis to study the effects of CFH deficiency.
• Examined CFH expression and C3 consumption in monocyte-derived inflammatory macrophages.
• Assessed plaque necrosis, efferocytosis, and plaque size in CFH-deficient and wild-type mice.
• Analyzed human atherosclerotic plaques for the presence of C3 and CFH in macrophages.

Main Results:

• CFH deficiency in a mouse model of atherosclerosis limited plaque necrosis in a C3-dependent manner.
• Deletion of CFH in macrophages led to uncontrolled intracellular C3 consumption, enhanced efferocytosis, and reduced plaque size.
• CFH expression was found in monocytes and macrophages, increasing during inflammation and correlating with intracellular C3 accumulation.
• Human atherosclerotic plaques contained monocyte-derived macrophages expressing both C3 and CFH.

Conclusions:

• CFH plays a critical role in regulating intracellular C3 levels within macrophages in a cell-autonomous manner.
• Macrophage-derived CFH dampens inflammation resolution and impairs efferocytosis.
• Targeting this CFH-macrophage regulatory axis may offer therapeutic strategies for inflammatory diseases like atherosclerosis.