SNX10 deficiency restricts foam cell formation and protects against atherosclerosis by suppressing CD36-Lyn axis.

Abstract Background Atherosclerosis-related cardiovascular diseases are among the leading causes of mortality worldwide. Uptake of modified lipoproteins by monocyte-derived macrophages leads to the formation of foam cells, which by secreting pro-inflammatory cytokines accelerate plaque development. Sorting Nexin 10 (SNX10) plays a critical role in the regulation of macrophage functions as well as in the lipid metabolism. This study aims to explore the precise effects and the underlying molecular mechanisms of SNX10 mediated processes in atherosclerotic diseases. Methods SNX10 knockout mice were generated and bone marrow-derived macrophages (BMDMs) were studied in vitro. Mice were crossed with apolipoprotein E-deficient (ApoE-/-) mice and atherogenesis was monitored for 16 weeks. Results Expression of SNX10 was increased in atherosclerotic plaques from both humans and ApoE-/- mice. SNX10 deficiency decreased foam cell abundance and alleviated atherosclerotic plaque progression in ApoE-/- mice. In addition, high fat, high cholesterol diet fed ApoE-/- mice contained more Ly6ChiCX3CR1lo monocytes than ApoE-/- SNX10-/- (DKO) littermates. ApoE-/- mice showed a higher level of inflammatory macrophages infiltrating into atherosclerotic lesions. SNX10 deficiency reduced the interactions between CD36 and Lyn, thus inhibiting CD36-mediated lipoprotein uptake and foam cell formation. Conclusions Our findings demonstrate CD36-Lyn dependent non-redundant atherogenic role for SNX10 in diet-induced atherogenesis. We propose SNX10 as a potential therapeutic target for the prevention and treatment of atherosclerosis.