Macrophage Deficiency of Sorting Nexin 25 Suppress Plaque Formation in Atherosclerotic Lesions in Mice.

Abstract

SNX25 is a member of the sorting nexin (SNX) superfamily, which plays crucial roles in membrane trafficking, cell signaling, and organelle dynamics. Our research has focused extensively on SNX25, demonstrating that SNX25-positive macrophages participate in inflammatory responses and pain perception through various signaling pathways. Atherosclerosis is now widely recognized as a chronic inflammatory disease of the vasculature, with macrophages serving as central contributors to its progression. These macrophages accumulate after internalizing oxidized low-density lipoproteins (oxLDL), transforming into foam cells that elicit inflammatory responses and promote atherosclerotic progression. To explore the impact of SNX25 on atherosclerosis, we induced the condition in apolipoprotein E-deficient (APOE^-/-) mice using a high-fat diet. As expected, SNX25 expression was observed in macrophages within atherosclerotic plaques. In SNX25^+/- mice on an APOE^-/- genetic background, plaque size was significantly smaller than in their SNX25^+/+ counterparts. Furthermore, bone marrow transplantation from SNX25^+/- mice into APOE^-/- recipients resulted in a marked reduction in foam cell formation and accumulation compared to transplants from SNX25^+/+ donors. These histopathological findings suggest that SNX25 may regulate macrophage activity under pathological conditions, identifying a novel role for SNX25 in the pathogenesis of atherosclerosis.