MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

Area of Science:

• Cardiovascular Biology
• Immunology
• Atherosclerosis Research

Background:

• Atherothrombotic vascular disease involves atherosclerotic lesions with impaired inflammation resolution, characterized by necrotic cores and thin fibrous caps.
• Defective efferocytosis (clearance of apoptotic cells) by macrophages is a key driver of plaque necrosis, but underlying mechanisms remain unclear.
• Understanding these mechanisms is crucial for developing strategies to promote resolution and prevent plaque complications.

Purpose of the Study:

• To investigate the role of proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) in atherosclerosis.
• To determine if MerTK cleavage contributes to plaque necrosis and impaired inflammation resolution.
• To explore the therapeutic potential of targeting MerTK cleavage in atherosclerotic disease.

Main Methods:

• Analysis of human carotid plaques to correlate MerTK cleavage with plaque necrosis and ischemic symptoms.
• Utilized fat-fed LDL receptor-deficient (Ldlr-/-) mice expressing a cleavage-resistant MerTK variant in myeloid cells.
• Assessed lesion characteristics, efferocytosis efficiency, and lipid mediator profiles in genetically modified mice.

Main Results:

• MerTK cleavage was observed in human carotid plaques and correlated with necrosis and ischemic symptoms.
• In mice, preventing MerTK cleavage led to higher macrophage MerTK, improved efferocytosis, and reduced necrotic core size.
• Lesions in mice with cleavage-resistant MerTK showed thicker fibrous caps and a shift towards proresolving lipid mediators.

Conclusions:

• Proteolytic cleavage of MerTK is a molecular mechanism that impairs macrophage efferocytosis in atherosclerosis.
• This defective efferocytosis promotes plaque necrosis and hinders inflammation resolution, contributing to disease progression.
• Targeting MerTK cleavage represents a potential therapeutic strategy for stabilizing atherosclerotic plaques and preventing vascular events.