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

• Published in: Biochimica et biophysica acta 2013-02, Vol.1831 (2), p.378-386
• Main Authors: Chu, Eugene M., Tai, Daven C., Beer, Jennifer L., Hill, John S.
• Format: Article
• Language: English
• Subjects: agonists; atherosclerosis; CD36; Cell Line; Cholesterol; Cholesterol - metabolism; Flow Cytometry; gene expression; homeostasis; Humans; Interferon γ; interferon-gamma; Lipoproteins, LDL - pharmacology; low density lipoprotein; Macrophage; Macrophage Activation; Macrophage scavenger receptor I; macrophages; Macrophages - metabolism; messenger RNA; Peroxisome proliferator-activated receptor γ; phenotype; protein synthesis; transcription factors; tumor necrosis factor-alpha
• ISSN: 1388-1981; 0006-3002; 1879-2618; 1878-2434
• DOI: 10.1016/j.bbalip.2012.10.009

Macrophages are centrally involved during atherosclerosis development and are the predominant cell type that accumulates cholesterol in the plaque. Macrophages however, are heterogeneous in nature reflecting a variety of microenvironments and different phenotypes may be more prone to contribute towards atherosclerosis progression. Using primary human monocyte-derived macrophages, we sought to evaluate one aspect of atherogenic potential of different macrophage phenotypes by determining their propensity to associate with and accumulate oxidized low density lipoprotein (oxLDL). Classically-activated macrophages treated simultaneously with interferon γ (IFNγ) and tumor necrosis factor α (TNFα) associated with less oxLDL and accumulated less cholesterol compared to untreated controls. The combined treatment of IFNγ and TNFα reduced the mRNA expression of CD36 and the expression of both cell surface CD36 and macrophage scavenger receptor 1 (MSR1) protein. Under oxLDL loaded conditions, IFNγ and TNFα did not reduce macrophage protein expression of the transcription factor peroxisome proliferator-actived receptor γ (PPARγ) which is known to positively regulate CD36 expression. However, macrophages treated with IFNγ attenuated the ability of the PPARγ-specific agonist rosiglitazone from upregulating cell surface CD36 protein expression. Our results demonstrate that the observed reduction of cholesterol accumulation in macrophages treated with IFNγ and TNFα following oxLDL treatment was due at least in part to reduced cell surface CD36 and MSR1 protein expression. ► We polarize human monocyte-derived macrophages (MDMs) to various sub-phenotypes. ► We test the propensity of different MDM sub-phenotypes to accumulate cholesterol. ► IFNγ or TNFα treatment reduces total cholesterol accumulation. ► Treatment with either IFNγ or TNFα reduces the expression of both CD36 and SR-AI. ► IFNγ attenuates the PPARγ-mediated upregulation of CD36.