The role of PPAR-γ in macrophages from atherosclerotic lesions is controversial. TZDs were shown to inhibit atherogenesis in LDL-R KO and ApoE KO mouse models [
44,
45] and to reduce carotid artery wall thickness in diabetic patients [
46]. However,
in vivo impact of TZDs in atherosclerosis depends on mechanisms involving multiple cell targets apart from macrophages, such as inhibition of endothelial activation [
45], inhibition of vascular smooth muscle cell proliferation [
47], reduction of vascular resistance and blood pressure [
48], increased insulin sensitivity and adiponectin production [
8], and anti-oxidant properties [
49]. Moreover, although PPAR-γ may limit atherogenesis at initial phases, serious doubts arise about its role in plaque instability. In fact, rosiglitazone was ultimately reported to increase the risk of myocardial infarction in diabetic patients [
50,
51], leading to its withdrawal from the market in several countries. Plaque instability is favored by enlargement of necrotic core in atherosclerotic lesions. Cholesterol-laden macrophages undergo apoptosis, and apoptotic macrophages turn into secondary necrotic cells if not promptly cleared [
52,
53]. Macrophage-specific PPAR-γ might have atherogenic potential by driving phagocytosis of oxLDLs
via CD36. PPAR-γ is in fact inducible by oxLXLs themselves, and is expressed in
M1-like macrophage foam cells of human atherosclerotic lesions [
23]. On the other side, LXRs, MerTK and CD163 seem to prevent plaque instability. LXRs protect against foam cell formation, by inducing ABC transporter-mediated cholesterol efflux [
9] and by upregulating MerTK in mice [
20] and in humans (as shown in this paper). MerTK, in turn, inhibits uptake of lipoproteins [
54] shifting phagocytosis activity toward efficient and non-inflammatory clearance of cholesterol-laden apoptotic macrophages [
52]. Additionally, both LXRs and MerTK exert anti-apoptotic effects on macrophages [
31,
33,
55]. CD163 exerts beneficial effects owing to upregulation of heme oxygenase-1 in response to hemoglobin-haptoglobin complexes, which ultimately results in iron clearance and prevention of oxidative reactions, along with release of IL-10 and anti-inflammatory heme metabolites [
56]. LXR-α and MerTK were demonstrated to be atheroprotective in LDL-R KO and ApoE KO mouse models [
52,
53,
57]. In humans, non-foamy protective
M2-like CD206
+ macrophages expressing high levels of MerTK [
26,
58] and CD163 [
59,
60] have been described in areas of plaques far from the necrotic core and close to microvessels or microhemorrhages, respectively. We hypothesize that the potential atherogenic role of PPAR-γ may become explicit in the presence of IL-4 or other PPAR-γ agonists like TZDs. IL-4 can in fact amplify PPAR-γ expression induced by oxLDLs [
13], and at the same time down-regulate LXR expression, so that PPAR-γ activation of LXRs is impaired [
26]. In this setting, macrophage uptake of lipoproteins is not followed by cholesterol efflux, thereby facilitating foam cell formation. Moreover, chronic stimulation with IL-4 and PPAR-γ activation induce apoptosis in macrophages [
33,
61], while IL-4 down-regulation of MerTK and CD163 [
4] may interfere with the clearance of apoptotic macrophages and iron, respectively. In fact, in both LDL-R KO and ApoE KO mice, IL-4 proved to extend the size of atherosclerotic lesions [
62,
63]. Taking together our present findings and previously reported data, we suggest that new PPAR-γ agonists not affecting macrophage-specific PPAR-γ might overcome controversial effects and cardiovascular safety concerns of TZDs. On the other hand, treatments apt to elicit the expansion of MerTK
+ and CD163
+ cells (e.g., M2c polarizing agents and IL-4/STAT-6 inhibitors) may help against atherosclerosis progression.