Platelet-Derived MRP-14 Induces Monocyte Activation in Patients With Symptomatic Peripheral Artery Disease

Background Peripheral Artery Disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear. Objectives To investigate the role of platelets in a cohort of symptomatic PAD. Methods We profiled platelet activity, mRNA and effector roles in patients with symptomatic PAD and healthy controls. Results Platelet RNASeq profiling mapped a robust upregulation of myeloid-related protein 14 (MRP-14) mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin thereby promoting platelet–monocyte aggregates (MPA). Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and co-localization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes thereby fueling their expression of key PAD lesional hallmarks and increased their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events. Conclusions We idenitified a heightened platelet activity profile and unraveled a novel immuno-modulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD.