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Conjugated linoleic acid induces an atheroprotective macrophage MΦ2 phenotype and limits foam cell formation.

de Gaetano M, Alghamdi K, Marcone S, Belton O - J Inflamm (Lond) (2015)

Bottom Line: However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.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.The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

ABSTRACT

Background: 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. 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.

Methods: Here, 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.

Results: cis-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.

Conclusion: The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

No MeSH data available.


Related in: MedlinePlus

CLA primes monocytes to an anti-inflammatory MΦ2 macrophage phenotype. RT-PCR analysis of (a)CD14 and CD68 and (b)CD163 and MR mRNA expression in or M-CSF stimulated (100 ng/ml) differentiating HPBMCs following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG. In unstimulated conditions, both CLA isomers and their blend decrease CD14 expression and increase expression of both CD163 and MR, without affecting CD68 expression. Following M-CSF stimulation, c-9,t-11-CLA and CLA blend decrease the mature macrophage marker CD68 and increase expression of both CD163 and MR (MΦ2 markers). Data are mean +/− SEM of three independent experiments. Data is expressed as fold change in gene expression relative to DMSO control, where *p < 0.05; ** p < 0.01 and ***p < 0.001 vs DMSO.
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Fig1: CLA primes monocytes to an anti-inflammatory MΦ2 macrophage phenotype. RT-PCR analysis of (a)CD14 and CD68 and (b)CD163 and MR mRNA expression in or M-CSF stimulated (100 ng/ml) differentiating HPBMCs following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG. In unstimulated conditions, both CLA isomers and their blend decrease CD14 expression and increase expression of both CD163 and MR, without affecting CD68 expression. Following M-CSF stimulation, c-9,t-11-CLA and CLA blend decrease the mature macrophage marker CD68 and increase expression of both CD163 and MR (MΦ2 markers). Data are mean +/− SEM of three independent experiments. Data is expressed as fold change in gene expression relative to DMSO control, where *p < 0.05; ** p < 0.01 and ***p < 0.001 vs DMSO.

Mentions: To elucidate if the atheroprotective CLA blend (80:20 c-9,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 MΦ2-type macrophage markers mannose receptor (MR) and CD163 (Figure 1b) in unstimulated or M-CSF-stimulated HPBMCs. Unstimulated monocyte cells were maintained in culture for 6 days, as a model of early macrophage differentiation, and M-CSF treated HPBMCs were used as a model of mature differentiated macrophages. Following 6 days of culture, unstimulated and M-CSF-stimulated macrophages were treated with 10 μM cis-9,trans-11-CLA (c-9,t-11-CLA), trans-10,cis-12-CLA (t-10,c-12-CLA), CLA blend (80:20 c-9,t-11:t-10,c-12), linoleic acid (LA), oleic acid or 5 μM of the PPARγ agonist, troglitazone (TROG) and analysed for expression of macrophage markers by RT-PCR and fluorescent microscopy.Figure 1


Conjugated linoleic acid induces an atheroprotective macrophage MΦ2 phenotype and limits foam cell formation.

de Gaetano M, Alghamdi K, Marcone S, Belton O - J Inflamm (Lond) (2015)

CLA primes monocytes to an anti-inflammatory MΦ2 macrophage phenotype. RT-PCR analysis of (a)CD14 and CD68 and (b)CD163 and MR mRNA expression in or M-CSF stimulated (100 ng/ml) differentiating HPBMCs following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG. In unstimulated conditions, both CLA isomers and their blend decrease CD14 expression and increase expression of both CD163 and MR, without affecting CD68 expression. Following M-CSF stimulation, c-9,t-11-CLA and CLA blend decrease the mature macrophage marker CD68 and increase expression of both CD163 and MR (MΦ2 markers). Data are mean +/− SEM of three independent experiments. Data is expressed as fold change in gene expression relative to DMSO control, where *p < 0.05; ** p < 0.01 and ***p < 0.001 vs DMSO.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4340802&req=5

Fig1: CLA primes monocytes to an anti-inflammatory MΦ2 macrophage phenotype. RT-PCR analysis of (a)CD14 and CD68 and (b)CD163 and MR mRNA expression in or M-CSF stimulated (100 ng/ml) differentiating HPBMCs following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG. In unstimulated conditions, both CLA isomers and their blend decrease CD14 expression and increase expression of both CD163 and MR, without affecting CD68 expression. Following M-CSF stimulation, c-9,t-11-CLA and CLA blend decrease the mature macrophage marker CD68 and increase expression of both CD163 and MR (MΦ2 markers). Data are mean +/− SEM of three independent experiments. Data is expressed as fold change in gene expression relative to DMSO control, where *p < 0.05; ** p < 0.01 and ***p < 0.001 vs DMSO.
Mentions: To elucidate if the atheroprotective CLA blend (80:20 c-9,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 MΦ2-type macrophage markers mannose receptor (MR) and CD163 (Figure 1b) in unstimulated or M-CSF-stimulated HPBMCs. Unstimulated monocyte cells were maintained in culture for 6 days, as a model of early macrophage differentiation, and M-CSF treated HPBMCs were used as a model of mature differentiated macrophages. Following 6 days of culture, unstimulated and M-CSF-stimulated macrophages were treated with 10 μM cis-9,trans-11-CLA (c-9,t-11-CLA), trans-10,cis-12-CLA (t-10,c-12-CLA), CLA blend (80:20 c-9,t-11:t-10,c-12), linoleic acid (LA), oleic acid or 5 μM of the PPARγ agonist, troglitazone (TROG) and analysed for expression of macrophage markers by RT-PCR and fluorescent microscopy.Figure 1

Bottom Line: However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.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.The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

ABSTRACT

Background: 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. 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.

Methods: Here, 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.

Results: cis-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.

Conclusion: The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

No MeSH data available.


Related in: MedlinePlus