Chitinase-like proteins de-N-glycosylating CD36 modify cholesterol metabolism in atherosclerotic macrophages.

Summary

This study uncovers that CHIL3/CHI3L2 act as glycosidases to de-N-glycosylate CD36 at N220/N321, boosting lipid uptake, activating mTOR, suppressing PPARγ, and impairing ABCG1-mediated efflux—thereby driving foam cell formation and atherogenesis. Neutralizing CHI3L2 prevented and treated atherosclerosis, nominating a druggable CLP–CD36 axis.

Key Findings

• CHIL3/CHI3L2 bind CD36 and enzymatically de-N-glycosylate it (notably at N220 and N321), enhancing lipid uptake in macrophages.
• Increased lipid influx activates mTOR, induces proinflammatory reprogramming, suppresses PPARγ, and impairs ABCG1-mediated cholesterol efflux.
• Single-cell sequencing shows expansion of foamy macrophages and VSMC transdifferentiation to foam/osteoblast-like cells in plaques.
• Neutralizing CHI3L2 antibodies both prevented and treated atherosclerosis in vivo.

Clinical Implications

CHI3L2 may serve as a therapeutic target and biomarker in atherosclerosis; anti-CHI3L2 therapy could complement lipid-lowering to reduce plaque progression and destabilization.

Limitations

• Preclinical models; human translational validation and safety of chronic CLP inhibition remain to be established.
• Potential off-target effects of glycosidase activity and long-term immunometabolic consequences are unknown.

Future Directions

Validate CHI3L2 as a biomarker/target in human cohorts; develop clinically viable antagonists/antibodies; assess synergy with statins/PCSK9i; evaluate plaque stabilization in large animals and early-phase trials.