Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis

Abstract

Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In <i>Ldlr</i> ^-/- mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the <i>Socs1:Socs3</i> ratio. Platelet-induced <i>Socs3</i> expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (<i>Il6</i>, <i>Il1b</i>, and <i>Tnfa</i>) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of <i>SOCS3</i>, lower <i>SOCS1:SOCS3</i>, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that <i>SOCS3</i> and the <i>SOCS1:SOCS3</i> ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, <i>SOCS3</i>, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.