*2.2.3. Macrophage polarization*

Macrophages are essential factors that contribute to the expression of inflammatory mediators and altered metabolism playing a critical role during the pathogenesis of atherosclerosis [69]. Polarized macrophages toward M1 phenotype aggravate atherosclerosis. The polarized macrophages not only exhibit increased inflammatory profile as observed in the expression of CCL2 and CCL5 but also change cholesterol homeostasis. The scavenger receptor class B type I (SR-B1) plays an important role in mediating the uptake of high-density lipoproteins (HDL) derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues, and its expression is reduced by M1 macrophages [70]. In addition, HDL prevents the induction of human macrophages into an M1 phenotype by preventing the accumulation of caveolin-1 to the cell membrane [71].

Adipokines play an important role particularly in the context of obesity and diabetes. Some have a direct vascular effect such as leptin and adiponectin [8, 72]. Increasing attention has been paid to the direct vascular effects of adipokines, especially adiponectin. Adiponectin is the most abundant adipokine secreted by adipose cells, which may couple the regulation of insulin sensitivity with energy metabolism as well as regulation of vascular function [8]. We have recently shown that adiponectin normalized endothelial cell function by a mechanism that involved increased eNOS phosphorylation and decreased perivascular adipose tissue inflammation [8]. In addition, hypoadiponectinemia-induced NLRP3 inflammasome was recently suggested as a novel mechanism of diabetic vascular endothelial dysfunction [73].

Some adipokines mediate the polarization of pro-inflammatory M1 and anti-inflammatory M2 macrophages and the influence of inflammation in the diabetic milieu. For instance, adiponectin and secreted frizzled-related protein 5 are both adipokines that have anti-inflammatory properties and that can stimulate M2 polarization [74, 75]. Both M1 and M2 macrophage phenotypes interchange dynamically depending on the environment. Depending on the stimulus, macrophages become polarized, which allows macrophages to critically contribute to tissue homeostasis, as they promote initiation and resolution of inflammatory responses. As a consequence, deregulation of the tissue macrophage polarization balance is an etiological agent of chronic inflammation present in obesity and insulin resistance [76].

In addition, it was previously reported that vitamin D promotes an antiatherogenic monocyte/macrophage phenotype in patients with diabetes [77]. Higher serum 25(OH)D levels correlated positively with a beneficial M2/M1 ratio, suggesting antiatherogenic properties [78]. Moreover, reversibility of the proatherogenic macrophage phenotype by vitamin D supplementation highlights vitamin D sufficiency as a potential therapeutic target to reduce inflammation and diabetic complications [77].
