Yu Wang, Lei Zhang, Meiyang Fan, Xianbin Hou, Xiaomeng Li, Wentao Zhang, Wenbin Liu, Yong Li, Yi‐An Lu, Fei Li, Yanglong Guan, Yudan Wang, Bingyu Yuan, Xiaowei Li, Huilin Gong, Feng Ning, Xiaozhen Zhuo, Shemin Lu, Liesu Meng, Rikard Holmdahl, Wenhua Zhu
Polymorphisms of mouse chitinase-like protein 3 (Chil3), a member of the mammalian chitinase-like protein (CLP) family, have been demonstrated to be associated with inflammatory diseases by regulating lipid metabolism. However, the specific immunomodulatory impacts of CLPs, mainly mouse CHIL3 and its human functional homologue chitinase-3-like 2 (CHI3L2), on macrophage cholesterol metabolism and atherosclerosis have remained unclear. Here, we find CLPs (CHIL3 and CHI3L2) accelerate atherogenesis in a macrophage-dependent manner. Mechanistically, we identify an autocrine mechanism through which CLPs regulate cholesterol metabolism in macrophages. Macrophage-secreted CLPs exacerbate lipid uptake by binding to CD36. CLPs exhibit glycosidase activity, targeting and hydrolyzing N-glycosylated glycans on CD36, predominantly at sites N220 and N321, thereby enhancing lipid uptake. Increased lipid influx activates mTOR in macrophages, driving their transition to a pro-inflammatory phenotype while simultaneously suppressing peroxisome proliferator-activated receptor gamma (PPARγ) expression and thus impairing ABCG1-mediated cholesterol efflux. Single-cell sequencing reveals that CLPs increase atherosclerotic foamy macrophages, favoring vascular smooth muscle cells (VSMC) transformation into foam and osteoblast-like cells. Additionally, neutralizing antibodies targeting CHI3L2 prevent and treat atherosclerosis. These findings highlight the potential of CLPs as targets for disease diagnosis and therapy. Macrophages and lipid metabolism have an important function in atherosclerosis. Here, the authors characterise the function of chitinase-like protein 3 (CHIL3) or its human functional homologue chitinase-3-like 2 (CHI3L2), and show these proteins enhance atherogenesis in a macrophage dependent manner and function by hydrolysing glycans on CD36 which enhances lipid uptake, activates mTOR and inflammatory macrophage responses and suppresses PPARγ-ABCG1-mediated cholesterol efflux.