Junqi Wang, Liming Peng, Huan Wang, Di Liu, Wenting Yang, Fang Yan, Dianyuan Zhao, Chunhua Zhang, Ziliang He, Xiaoping Chen, Li Tang
The formation of foamy macrophages is often considered a pathological hallmark of atherosclerosis, but the underlying mechanisms remain elusive. Herein, we demonstrated that the transcription factor TFEC could upregulate the expression of Glycoprotein non-metastatic melanoma protein B (GPNMB) in atherosclerotic plaque foamy macrophages. Circulating levels of soluble GPNMB correlated positively with atherosclerotic severity. Moreover, mice with systemic Gpnmb-mutation or myeloid-specific Gpnmb knockout exhibited a reduced atherosclerotic burden. Live-cell imaging revealed that GPNMB-positive vesicles were involved in lipoprotein internalization and transport within macrophages and facilitated lipid droplet formation. In Gpnmb-mutant macrophages, impaired lipid droplet formation from internalized lipoproteins, combined with enhanced lipid β-oxidation and lysosomal lipolysis, led to reduced macrophage foaming. Notably, mice treated with siRNA-loaded lipid nanoparticles targeting Gpnmb in lesional foamy macrophages showed alleviation of atherosclerotic burden. Overall, our findings elucidate the intracellular lipoprotein processing in macrophages and suggest GPNMB as a potential therapeutic target for atherosclerosis. Foamy macrophages are key to atherosclerosis but poorly understood. Here, the authors show that GPNMB regulates lipoprotein processing in macrophages, exacerbating pathological lipid accumulation, and revealing it as a therapeutic target whose inhibition reduces atherosclerosis in mice.