Macrophage regulation in atherosclerosis

Atherosclerosis is the leading cause of cardiovascular disease, topping the mortality list in the United Kingdom and the rest of the world. Macrophage activation and polarisation are key steps in host defence and chronic inflammatory diseases, including atherosclerosis. The myeloid glycoprotein receptor CD200R1 belongs to a family of four isoforms and signals after binding to its cognate ligand, CD200. The CD200/CD200R1 interaction blocks pro-inflammatory cytokines and has never before been studied in atherosclerosis. My work has demonstrated that CD200R is weakly expressed in atherosclerotic lesions during disease progression and significantly down-regulated in secondary lymphoid organs. Moreover, changes in shear stress had no effect on the expression of CD200R in plaques. During the steady state, the expression of CD200R on circulating monocytes was highest on the CD11b+CD115+Ly6Cint subset, revealing a potential mechanism for regulation of maturing monocytes. In vitro studies demonstrated that CD200R expression is sensitive to M1 macrophage polarising cytokine IFN-γ and MyD88-dependent TLR ligands. In contrast, non-MyD88-dependent TLR3 signalling had no effect on its expression, supporting previous findings in the literature. Moreover, CD200R1 mRNA expression was induced on alternatively activated M2a macrophage subsets following IL-4 and IL-13 cytokine treatment, whereas oxLDL had no effect. Immunotherapy with CD200-Fc in ApoE-/- mice exerted no significant changes on lesion size and phenotype compared to controls after nine weeks. My findings indicate that the type of inflammatory stimulus may play a role in dictating the ability of myeloid cells to terminate their own activation via CD200/CD200R1 signalling. Hence, chronic inflammation may be promoted by reduced presence of inhibitory signals leading to sustained, unresolved inflammation. In summary, my work has revealed new insight into the regulation of the inhibitory CD200R pathway in atherosclerosis, the molecular signals that may affect the regulation of inflammation through CD200R and possible future therapeutic strategies.Open Acces