Pro-inflammatory monocyte-macrophage polarization imbalance in human hypercholesterolemia and atherosclerosis

•Monocytes may mediate the effects of hypercholesterolemia on atherosclerosis.•We found increased M1 and reduced M2 monocytes in hypercholesterolemic patients.•M1 and M1/M2 ratio were directly related to LDL and associated with atherosclerosis.•Thus, hypercholesterolemia may foster atherosclerosis by skewing M1 vs M2 monocytes.

Monocyte-macrophages (MoMas) play a major role in atherosclerosis. In mice, hypercholesterolemia increases pro-inflammatory monocytes that promote plaque growth, but whether this is true also in humans in unknown. We herein analyzed monocyte subsets and MoMa phenotypes in familiar (FH, n = 22) and non-familiar (NFH, n = 20) hypercholesterolemic compared with normocholesterolemic (CTRL, n = 20) patients. We found that FH and NFH had higher circulating pro-inflammatory CD68+CCR2+ M1 MoMas than CTRL, while anti-inflammatory CX3CR1+CD163+/CD206+ M2 MoMas were reduced only in NFH. As a result, the M1/M2 polarization balance was increased in FH and, more markedly in NFH. M1 MoMas and the M1/M2 polarization ratio were directly correlated to pre-treatment LDL cholesterol levels and strongly associated with the presence of atherosclerotic plaques. In conclusion, we show for the first time that human hypercholesterolemia is associated with a pro-inflammatory imbalance of circulating monocytic cells, which can predispose to the development of atherosclerosis.