Modulation of Macrophage Phenotype by Platelets and Cyclophilin A in Cardiovascular Inflammation

Atherosclerosis remains a leading cause of death worldwide, despite lipid-lowering therapies like statins. Given the vital role of macrophages in this disease, shifting their polarization towards protective phenotypes offers promising therapeutic potential. Macrophage plasticity highlights the importance of understanding how cellular interactions, such as with platelets, influence macrophage behavior. While platelets are known for their role in thrombosis, they are also immune modulators. The interaction between platelets and macrophages remains poorly understood and varies depending on the pathophysiological context. Cyclophilin A, secreted by activated platelets, is involved in cardiovascular diseases. This study shows that Cyclophilin A is secreted from platelets independently of its acetylation, contrasting previous findings in smooth muscle cells. Super-resolution microscopy confirmed its surface expression on platelets, which correlates with poor cardiovascular outcomes. We further explored how platelet-derived Cyclophilin A influences macrophages via the TREM2 receptor, finding that both platelets and Cyclophilin A drive macrophages towards a pro-inflammatory state. Our study also identified that recurrent platelet contact and fibrin(-ogen) exposure altered macrophage gene expression, resembling the protective phenotype of aortic intimal resident macrophages. These findings suggest new mechanisms by which platelet and macrophage interactions contribute to vascular homeostasis, with potential therapeutic implications.