GM-CSF Deficiency Reduces Macrophage PPAR-γ Expression and Aggravates Atherosclerosis in ApoE-Deficient Mice

Abstract

Objective— Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in atherosclerotic lesions but its significance for lesion development is unknown. Consequently, we investigated the significance of GM-CSF expression for development of atherosclerotic lesions in apolipoprotein E-deficient (apoE −/− ) mice. Methods and Results— We generated apoE −/− mice deficient in GM-CSF (apoE −/− .GM-CSF −/− mice), fed them a high-fat diet, and compared lesion development with apoE −/− mice. We measured lesion size, macrophage, smooth muscle cell, and collagen accumulation at the aortic sinus, and expression of genes that regulate cholesterol transport and inflammation. No differences in serum cholesterol were found between the 2 groups. Lesion size in hyperlipidemic apoE −/− .GM-CSF −/− increased by 30% ( P <0.05), macrophage accumulation doubled, and collagen content reduced by 15% ( P <0.05); smooth muscle cell accumulation and vascularity were unaffected. Analysis of PPAR-γ, ABCA1, and CD36 in lesions showed reduced expression (50%, 65%, and 55%, respectively), whereas SR-A doubled. In peritoneal macrophages, PPAR-γ and ABCA1 expression was also reduced by 50% and 70%, respectively, as was cholesterol efflux, by 50%. In lesions, pro-inflammatory MCP-1 and tumor necrosis factor (TNF)-α expression increased 2- and 3.5-fold, respectively, vascular cell adhesion molecule (VCAM)-1 expression enhanced and interleukin (IL)-1 receptor antagonist reduced by 50%. Conclusions— GM-CSF deficiency increases atherosclerosis under hypercholesterolemic conditions, indicating antiatherogenic role for GM-CSF. We suggest this protective role is mediated by PPAR-γ and ABCA1, molecules that affect cholesterol homeostasis and inflammation.

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

“…Elevated serum levels of these cytokines are generally found in patients having a poor prognosis or more severe arterial lesions (55,56). Animal models designed to decipher the role of IL-6, TNF-a, and GM-CSF in atherosclerosis have not yet been fully conclusive because experimental settings (feeding diet, location of the lesions, and sex of the animals) largely determine the outcome of lesion evolution (57)(58)(59)(60)(61)(62)(63)(64). In this study we show that IL-6, TNF-a, and GM-CSF production is inconstant but characteristic of resident B cells, whereas the lack of expression of the other tested cytokines is a permanent feature.…”

A novel model of cholesterol efflux from lipid-loaded cells

“…However, PPAR-γ does not promote the formation of foam cells. Activated PPAR-γ inhibits the formation of macrophagederived foam cells and decreases the accumulation of triglycerides in macrophages treated with triglyceride-rich lipoproteins by downregulating SR-A and apo-B48 [68,69] . PPAR-γ enhances cholesterol efflux and attenuates atherosclerosis by inducing caveolin-1 expression in apo-E-deficient mice [70] .…”

Nuclear receptors in macrophages: A link between metabolism and inflammation

“…Mice deficient in M-CSF are relatively resistant to atherosclerosis [67,68]. Both granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF) increase lesion formation when administered to ApoE knockout mice [69][70][71]. At the same time GM-CSF deficiency reduces PPAR-c expression and aggravates atherosclerosis in ApoE knockout mice [70].…”