P96Expression of the regulatory receptor CD200R on macrophages is regulated by polarization signals in atherosclerosis

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Abstract

Background

Macrophage activation and polarization are key steps in host defense and chronic inflammatory diseases, including atherosclerosis. The glycoprotein receptor CD200R1 belongs to a family of four isoforms and signals by binding to its counterpart ligand CD200. The receptor is expressed on cells of the myeloid lineage and inhibits inflammatory signaling by blocking pro-inflammatory mediators.

Aims

Our work aims to determine the signals that regulate CD200R expression during macrophage polarization and the development of atherosclerosis.

Methods

Bone marrow-derived macrophages from WT mice were cultured in the presence of combinations of Interferon gamma (IFN-g), Lipopolysaccharide (LPS) (pro-inflammatory M1 macrophages) or IL-4 and IL-13 (M2 macrophages). The expression of CD200R1 and polarization markers was evaluated via Q-PCR. Using the hypercholesterolaemic ApoE-/- model which spontaneously develops atherosclerotic lesions, we assessed the kinetics of CD200R1 expression (at 8, 12-15 and 35 weeks of age) during disease progression in the aorta and in secondary lymphoid organs with immunohistochemistry and Q-PCR.

Results

CD200R1 gene expression is significantly reduced after exposure to M1 signals IFN-g and LPS alone (respectively 3 ± 0.09 fold change; p < 0.001 and 2.38 ± 0.05; p < 0.01 vs. un-stimulated) or in combination (6.02 ± 0.039, p < 0.001). A similar pattern is followed by the M2 marker CD206 (1.78 ± 0.11, p < 0.05). Conversely, IL-4 and IL-13 increased expression of CD200R1 using IL-4 alone (2.83 ± 0.41, p < 0.05) or IL-4 together with IL-13 (2.3 ± 0.38, p < 0.05). This correlated with the increased expression of CD206 p < 0.01. Treatment with oxidized low-density lipoprotein (oxLDL) did not induce significant changes. Finally, CD200R1 expression in ApoE-/- mice is reduced at late stages of atherosclerosis compared to healthy age matched controls (p < 0.05)

Conclusion

The expression of CD200R1 is negatively regulated by pro-inflammatory M1 signals and positively regulated by anti-inflammatory M2 signals. CD200R1 is also reduced at late stages of atherosclerosis. The CD200R-CD200 axis could be failing to regulate inflammation in atherosclerosis.

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