Chitinase-3-like Protein 1 Reduces the Stability of Atherosclerotic Plaque via Impairing Macrophagic Efferocytosis

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Chitinase-3-like protein 1 (CHI3L1) is linked to atherosclerosis.
• The specific role of CHI3L1 in macrophage function within atherosclerotic plaques is not well understood.

Purpose of the Study:

• To investigate the role of CHI3L1 in macrophage efferocytosis and its impact on atherosclerotic plaque stability.
• To elucidate the molecular mechanisms by which CHI3L1 influences efferocytosis and plaque pathology.

Main Methods:

• Analysis of CHI3L1, ATF2, and MFGE8 expression in human carotid plaques and serum.
• In vitro studies on macrophage efferocytosis.
• In vivo experiments using Ldlr-/- mice with induced atherosclerosis, treated with CHI3L1 protein or a CHI3L1 blocking antibody.

Main Results:

• CHI3L1 was upregulated in symptomatic atherosclerotic plaques and serum.
• CHI3L1 inhibited macrophage efferocytosis by down-regulating MFGE8 expression via ATF2 inhibition.
• In vivo, CHI3L1 administration enlarged necrotic cores and reduced MFGE8/ATF2 levels, while antibody treatment showed opposite effects.
• Negative correlations between CHI3L1, ATF2, and MFGE8 levels were observed in human plaques.

Conclusions:

• CHI3L1 destabilizes atherosclerotic plaques by impairing macrophage efferocytosis through the downregulation of ATF2-induced MFGE8.
• Targeting CHI3L1 presents a potential therapeutic strategy for atherosclerosis treatment.