CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis.
Kassiteridi C., Cole JE., Griseri T., Falck-Hansen M., Goddard ME., Seneviratne AN., Green PA., Park I., Shami A., Pattarabanjird T., Upadhye A., Taylor AM., Handa A., Channon KM., Lutgens E., McNamara CA., Williams RO., Monaco C.
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 CVD. The role of this pathway in CVD is unknown. Objective: We sought to examine the role of CD200 in atherosclerosis. Methods and Results: Using hypercholesterolemic ApoE-/- 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 Ly6Chi monocytes and CCR2+ macrophages within the atherosclerotic aorta, as assessed by mass cytometry. Moreover, we uncover a previously uncharacterised effect of the CD200/CD200R pathway in limiting dysregulated monopoiesis and Ly6Chi monocytosis in hypercholesterolemic mice. Bone marrow chimera experiments demonstrate that the CD200-CD20R pathway enables two complementary and tissue-dependent strategies to limit atherogenesis: CD200 expression by bone-marrow derived cells limits systemic monocytosis, while CD200 expression by non-haematopoietic cells, e.g. endothelial cells, prevents local plaque growth. We show that CD200R signalling controls monopoiesis and macrophage activation through inhibiting phosphorylation of STAT1. Finally, CD200R expression on classical monocytes in peripheral blood of patients with coronary artery disease (CAD) is associated with a lower burden of CAD and a more favourable 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 CVD.