CHI3L1 is strongly associated with atherosclerosis, but its role in macrophages remains unknown. In this study, we observed a significant up-regulation of CHI3L1 in both carotid plaques and serum of symptomatic patients, and demonstrated that CHI3L1 impairs the efferocytosis of macrophages by down-regulating crucial efferocytic mediator MFGE8 through inhibiting ATF2, which binds directly to the enhancer of MFGE8. In human plaques, we observed a negative correlation between CHI3L1 expression and both ATF2 and MFGE8 levels, further proved their involvement in plaque destabilization. Using Ldlr-/- mice with tandem carotid stenosis surgery, we demonstrated that administration of CHI3L1 protein resulted in enlarged atherosclerotic necrotic cores and decreased MFGE8 and ATF2 levels. Conversely, treatment with a CHI3L1 blocking antibody exhibited the opposite trend.In conclusion, CHI3L1 destabilizes atherosclerotic plaque by impairing macrophagic efferocytosis through the down-regulation of ATF2-induced MFGE8 expression. Targeting CHI3L1 may offer a promising therapeutic strategy for the treatment of atherosclerosis.
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