PPARγ Activation Primes Human Monocytes into Alternative M2 Macrophages with Anti-inflammatory Properties

Abstract

Th1 cytokines promote monocyte differentiation into proatherogenic M1 macrophages, while Th2 cytokines lead to an "alternative" anti-inflammatory M2 macrophage phenotype. Here we show that in human atherosclerotic lesions, the expression of M2 markers and PPARgamma, a nuclear receptor controlling macrophage inflammation, correlate positively. Moreover, PPARgamma activation primes primary human monocytes into M2 differentiation, resulting in a more pronounced anti-inflammatory activity in M1 macrophages. However, PPARgamma activation does not influence M2 marker expression in resting or M1 macrophages, nor does PPARgamma agonist treatment influence the expression of M2 markers in atherosclerotic lesions, indicating that only native monocytes can be primed by PPARgamma activation to an enhanced M2 phenotype. Furthermore, PPARgamma activation significantly increases expression of the M2 marker MR in circulating peripheral blood mononuclear cells. These data demonstrate that PPARgamma activation skews human monocytes toward an anti-inflammatory M2 phenotype.

Macrophage heterogeneity and cholesterol homeostasis: Classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL

“…For example, classically activated macrophages exposed to IFNγ and microbial products such as LPS during bacterial infection are critical for efficient immune responses while alternatively activated macrophages have been shown to be important in the resolution of inflammation [37,38]. Both macrophage sub-phenotypes have been identified in human atherosclerosis and have been found to localize to unique areas of the plaque suggesting that they are involved in different processes [9,39,40]. Because of these differences in function, we sought to compare the ability of established macrophage sub-phenotypes to maintain cholesterol homeostasis.…”

“…Macrophages within the lesion are heterogeneous in nature and exhibit a variety of phenotypic states ranging from pro-inflammatory to anti-inflammatory [9]. These phenotypes are thought to be dynamic responses to their environment as their ability to switch from one phenotype to another has been demonstrated in vitro [10].…”

“…IL-4 stimulates the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPARγ) which has been shown to mediate alternative macrophage activation as well as the transcriptional repression of several pro-inflammatory transcription factors [9,[19][20][21]. PPARγ activation is partially responsible for the antagonization of several IFNγ-mediated activities such as the upregulation of TNFα, IL-12(p40), IL-1β, NO, and promoting T helper cell differentiation towards a Th1 phenotype [22][23][24][25][26].…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…Interestingly, a recent study suggests that antidiabetic effects of thiazolidinediones may be mediated, at least partly, through PPARγ in macrophages [33]. Moreover, both M1 and M2 markers are detected in circulating monocytes [34,35]. Prior to macrophage infiltration at the site of chronic inflammation, monocytes in obese and/or obese type 2 diabetic patients exhibit higher expression of M1 markers and lower expression of M2 markers than those in normal-weight controls, which is associated with arterial stiffness [34].…”

“…Prior to macrophage infiltration at the site of chronic inflammation, monocytes in obese and/or obese type 2 diabetic patients exhibit higher expression of M1 markers and lower expression of M2 markers than those in normal-weight controls, which is associated with arterial stiffness [34]. Interestingly, pioglitazone treatment significantly improves arterial stiffness along with the unbalanced M1/M2 phenotype of monocytes [34,35]. Collectively, phenotypic modulation of adipose tissue macrophages may offer a novel therapeutic strategy to prevent or treat the progression of obesity-induced complications such as diabetes and atherosclerosis.…”