CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis

Rationale: Inflammation is a basic component of the pathogenesis of atherosclerosis. CD200 is an immune checkpoint known to control macrophage activation. CD200 recently emerged in the Framingham Heart Study and 2 other cohorts as being potentially relevant in cardiovascular disease. The role of this pathway in cardiovascular disease is unknown. Objective: We sought to examine the role of CD200 in atherosclerosis. Methods and Results: Using hypercholesterolemic apolipoprotein-E deficient mice, we demonstrate that whole-body CD200 deficiency augments atherosclerotic lesion formation and vulnerability. Administration of a CD200-Fusion protein reduces neointima formation. Our data show that the CD200-CD200R pathway restrains activation of CD200R+ lesional macrophages, their production of CCR2 ligands, and monocyte recruitment in vitro and in vivo in an air pouch model. Loss of CD200 leads to an excessive accumulation of classical Ly6C^himonocytes and CCR2⁺macrophages within the atherosclerotic aorta, as assessed by mass cytometry. Moreover, we uncover a previously uncharacterized effect of the CD200/CD200R pathway in limiting dysregulated monopoiesis and Ly6C^himonocytosis in hypercholesterolemic mice. Bone marrow chimera experiments demonstrate that the CD200-CD20R pathway enables 2 complementary and tissue-dependent strategies to limit atherogenesis: CD200 expression by bone marrow-derived cells limits systemic monocytosis, while CD200 expression by nonhematopoietic cells, for example, endothelial cells, prevents local plaque growth. We show that CD200R signaling controls monopoiesis and macrophage activation through inhibiting phosphorylation of STAT1 (signal transducer and activator of transcription 1). Finally, CD200R expression on classical monocytes in peripheral blood of patients with coronary artery disease is associated with a lower burden of coronary artery disease and a more favorable Virtual Histology plaque profile. Conclusions: The CD200 checkpoint is a key-limiting factor for monopoiesis, monocyte-macrophage activation, and recruitment in atherosclerosis with conserved features in human and mouse. It thus offers a novel potential therapeutic pathway to treat cardiovascular disease.