Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF: Implication in atherosclerosis

Abstract

ObjectivesWe characterized the transcriptional profiles of GM-CSF- (GM-MØ) and M-CSF-induced macrophages (M-MØ) and investigated in situ a subset of differentially expressed genes in human and mouse atherosclerotic lesions. Methods and resultsUsing microarrays we identified a number of genes and biological processes differentially regulated in M-MØ vs GM-MØ. By varying in culture the M-CSF/GM-CSF ratio (0–10), a spectrum of macrophage phenotypes was explored by RT-QPCR. M-CSF (10ng/ml) stimulated expression of several genes, including selenoprotein-1 (SEPP1), stabilin-1 (STAB1) and CD163 molecule-like-1 (CD163L1) which was inhibited by a low dose of GM-CSF (1ng/ml); M-CSF inhibited the expression of pro-platelet basic protein (PPBP) induced by GM-CSF. Combining Tissue Microarrays/quantitative immunohistochemistry of human aortic lesions with RT-QPCR expression data either from human carotids vs mammary non-atherosclerotic arteries or from the apoE null mice normal and atherosclerotic aortas showed that, STAB1, SEPP1 and CD163L1 (M-CSF-sensitive genes) and PPBP (GM-CSF-sensitive gene) were expressed in both human arterial and apoE null mice atherosclerotic tissues. ConclusionA balance between M-CSF vs GM-CSF defines macrophage functional polarisation and may contribute to the progression of atherosclerosis.