Research ArticleAtherosclerosis

Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis

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Science Translational Medicine  06 Nov 2019:
Vol. 11, Issue 517, eaax0481
DOI: 10.1126/scitranslmed.aax0481

Platelets and plaques

Platelet activation promotes inflammation, and macrophage-platelet aggregates have been found in cardiovascular disease. Barrett et al. investigated the role of platelets in regulating macrophage polarization in atherosclerosis. Mice with high cholesterol had increased platelet-macrophage aggregates in atherosclerotic plaques, and platelets promoted monocyte recruitment to plaques. Platelets enhanced macrophage expression of myeloid suppressor of cytokine signaling 3 (SOCS3), promoting a proinflammatory phenotype with impaired phagocytosis. Depleting platelets in mice reduced plaque size and macrophage accumulation. SOCS3 was up-regulated, and SOCS1:SOCS3 expression inversely correlated with platelet activity in patients with myocardial infarction and cardiovascular disease. Results elucidate an atherogenic role of platelets via regulation of myeloid inflammation.


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 Ldlr−/− 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 Socs1:Socs3 ratio. Platelet-induced Socs3 expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (Il6, Il1b, and Tnfa) 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 SOCS3, lower SOCS1:SOCS3, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that SOCS3 and the SOCS1:SOCS3 ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, SOCS3, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.

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