Abstract
BackgroundAtherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds. We have previously shown that a specific CLA blend (80:20 cis-9,trans-11:trans-10,cis-12-CLA) induces regression of pre-established atherosclerosis in vivo, via modulation of monocyte/macrophage function. However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.MethodsHere, we address if CLA primes monocytes towards an anti-inflammatory MΦ2 macrophage and examine the effect of individual CLA isomers and the atheroprotective blend on monocyte-macrophage differentiation, cytokine generation, foam cell formation and cholesterol metabolism in human peripheral blood monocyte (HPBMC)-derived macrophages.Resultscis-9,trans-11-CLA and the atheroprotective 80:20 CLA blend regulates expression of pro-inflammatory mediators and modulates the inflammatory cytokine profile of macrophages and foam cells. In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression. Furthermore, this altered macrophage phenotype impacts on foam cell formation, inhibiting ox-LDL accumulation and promoting cholesterol efflux via both PPARγ and LXRα dependent pathways.ConclusionThe data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-015-0060-9) contains supplementary material, which is available to authorized users.
Highlights
Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role
Conjugated linoleic acid (CLA) primes human monocytes towards an MΦ2 phenotype To elucidate if the atheroprotective CLA blend (80:20 c9,t-11:t-10,c-12-CLA) impacts on monocyte-macrophage differentiation, we analysed the mRNA expression of the pan-monocyte and pan-macrophage markers, CD14 and CD68, respectively (Figure 1a), and of the MΦ2type macrophage markers mannose receptor (MR) and CD163 (Figure 1b) in unstimulated or M-CSFstimulated human peripheral blood monocyte (HPBMC)
Unstimulated monocyte cells were maintained in culture for 6 days, as a model of early macrophage differentiation, and macrophage colony-stimulating factor (M-CSF) treated HPBMCs were used as a model of mature differentiated macrophages
Summary
Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Cholesterol esters are stored in the cytosol or cleaved by the neutral cholesterol ester hydrolase to free cholesterol which is effluxed from the macrophage via several transporters, including ATP-binding cassette (ABC) family (ABCA-1, ABCG-1) and SR-B1 to acceptor molecules, such as apo-A1 and HDL for subsequent metabolism in the liver [8,9]. This reverse cholesterol transport (RCT) pathway is regulated by the nuclear receptor Liver X Receptor (LXR)
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