Abstract
Atherosclerosis is a chronic inflammatory disease driven by pathological processes such as macrophage foam cell formation. Semaphorin 7A (SEMA7A) is an immunoregulatory signaling molecule known to modulate immune responses and cellular adhesion. However, the contribution of macrophage-derived SEMA7A to atherogenesis has yet to be fully elucidated. In this study, we analyzed gene expression profiles of human mononuclear cells from the Gene Expression Omnibus (GEO) database and revealed highly expressed SEMA7A and its receptor integrin β1 in macrophages. The upregulation of SEMA7A and integrin β1 was also observed during the differentiation of THP-1 monocytes into macrophages. Mice with macrophage-specific deletion of Sema7a showed a 57.2% reduction in atherosclerotic lesion size and improved plaque stability in atherosclerosis mouse model compared to control mice. Mechanistically, macrophage SEMA7A promoted the expression of macrophage scavenger receptor 1 (MSR1) and lipid uptake mediated by integrin β1 and downstream JNK signaling pathway in macrophages. Notably, pharmacological inhibition of integrin β1 with integrin receptor antagonist GLPG0187 effectively suppressed atherosclerosis progression. These findings identify macrophage-derived SEMA7A as a key driver of atherosclerosis through a novel integrin β1/JNK/MSR1 axis, providing potential targets for the prevention and treatment of atherosclerosis.