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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 inhibits production of pro-inflammatory citokine secretion in human macrophages and foam cells. Measurement of cytokine released was quantified in HPBMC-derived (a) macrophages and (b) foam cells following treatment with c-9,t-11; t-10,c-12; CLA blend; OA; LA or TROG using a multiplex ELISA. Both individual CLA isomers and the CLA bend reduced pro-inflammatory cytokine generation via a PPARγ dependent mechanisms. Uniquely, c-9,t-11-CLA increased macrophage and foam cell generation of IL10, via a PPARγ independent mechanism. Data are expressed as % cytokine release over vehicle control and are the mean of three independent experiments where *p < 0.05, **p < 0.01, ***p < 0.001.
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Fig5: CLA inhibits production of pro-inflammatory citokine secretion in human macrophages and foam cells. Measurement of cytokine released was quantified in HPBMC-derived (a) macrophages and (b) foam cells following treatment with c-9,t-11; t-10,c-12; CLA blend; OA; LA or TROG using a multiplex ELISA. Both individual CLA isomers and the CLA bend reduced pro-inflammatory cytokine generation via a PPARγ dependent mechanisms. Uniquely, c-9,t-11-CLA increased macrophage and foam cell generation of IL10, via a PPARγ independent mechanism. Data are expressed as % cytokine release over vehicle control and are the mean of three independent experiments where *p < 0.05, **p < 0.01, ***p < 0.001.

Mentions: Using multiplex ELISA, we showed that pro-inflammatory cytokine generation was reduced in mature macrophages by CLA, in a similar manner to that of the PPARγ agonist (TROG) (Figure 5a). c-9,t-11-CLA significantly inhibited IL-6 and IL-1β generation (by 26 ± 10%,p < 0.01 and by 23 ± 2%, p < 0.05, respectively) and the CLA blend inhibited IL-1β, INF-γ and IL-12p70 (by 23 ± 5%,p < 0.05; by 20 ± 3%, p < 0.01 and by 36 ± 12%, p < 0.05, respectively). Interestingly, t-10,c-12-CLA also reduced IL-1β, INF-γ and IL-12p70 (by 30 ± 3%,p < 0.01; by 19 ± 8%, p < 0.05 and by 26 ± 11%, p < 0.05, respectively). Coincident with its role in macrophage polarisation, the PPARγ agonist inhibited all pro-inflammatory cytokines analysed. Importantly, c-9,t-11-CLA also increased anti-inflammatory cytokine IL-10 generation in macrophages (by 2.1 fold, p < 0.05), suggesting a specificity of this isomer to profoundly alter the cytokine profile of the marophage cells. Furthermore, we showed that the altered cytokine profile was maintained following stimulation of foam cell formation where pro-inflammatory cytokines generation was reduced by CLA, in a similar manner to that of the PPARγ agonist (TROG) (Figure 5b). In particular, c-9,t-11-CLA significantly inibited IL-6 and INF-γ generation (by 34 ± 15%, p < 0.05 and by 37 ± 12%, p < 0.05, respectively) and the CLA blend inibited IL-6, TNF-α and INF-γ (by 65 ± 4%,p < 0.001; by 42 ± 17%, p < 0.05; by 49 ± 6%, p < 0.01, respectively). t-10,c-12-CLA also reduced IL-6, TNF-α and IL-12p70 (by 51 ± 7%,p < 0.01; by 40 ± 16%, p < 0.05 and by 38 ± 17%, p < 0.05, respectively) and TROG reduced generation of IL-6, TNF-α, INF-γ and IL12p70.Figure 5


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 inhibits production of pro-inflammatory citokine secretion in human macrophages and foam cells. Measurement of cytokine released was quantified in HPBMC-derived (a) macrophages and (b) foam cells following treatment with c-9,t-11; t-10,c-12; CLA blend; OA; LA or TROG using a multiplex ELISA. Both individual CLA isomers and the CLA bend reduced pro-inflammatory cytokine generation via a PPARγ dependent mechanisms. Uniquely, c-9,t-11-CLA increased macrophage and foam cell generation of IL10, via a PPARγ independent mechanism. Data are expressed as % cytokine release over vehicle control and are the mean of three independent experiments where *p < 0.05, **p < 0.01, ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: CLA inhibits production of pro-inflammatory citokine secretion in human macrophages and foam cells. Measurement of cytokine released was quantified in HPBMC-derived (a) macrophages and (b) foam cells following treatment with c-9,t-11; t-10,c-12; CLA blend; OA; LA or TROG using a multiplex ELISA. Both individual CLA isomers and the CLA bend reduced pro-inflammatory cytokine generation via a PPARγ dependent mechanisms. Uniquely, c-9,t-11-CLA increased macrophage and foam cell generation of IL10, via a PPARγ independent mechanism. Data are expressed as % cytokine release over vehicle control and are the mean of three independent experiments where *p < 0.05, **p < 0.01, ***p < 0.001.
Mentions: Using multiplex ELISA, we showed that pro-inflammatory cytokine generation was reduced in mature macrophages by CLA, in a similar manner to that of the PPARγ agonist (TROG) (Figure 5a). c-9,t-11-CLA significantly inhibited IL-6 and IL-1β generation (by 26 ± 10%,p < 0.01 and by 23 ± 2%, p < 0.05, respectively) and the CLA blend inhibited IL-1β, INF-γ and IL-12p70 (by 23 ± 5%,p < 0.05; by 20 ± 3%, p < 0.01 and by 36 ± 12%, p < 0.05, respectively). Interestingly, t-10,c-12-CLA also reduced IL-1β, INF-γ and IL-12p70 (by 30 ± 3%,p < 0.01; by 19 ± 8%, p < 0.05 and by 26 ± 11%, p < 0.05, respectively). Coincident with its role in macrophage polarisation, the PPARγ agonist inhibited all pro-inflammatory cytokines analysed. Importantly, c-9,t-11-CLA also increased anti-inflammatory cytokine IL-10 generation in macrophages (by 2.1 fold, p < 0.05), suggesting a specificity of this isomer to profoundly alter the cytokine profile of the marophage cells. Furthermore, we showed that the altered cytokine profile was maintained following stimulation of foam cell formation where pro-inflammatory cytokines generation was reduced by CLA, in a similar manner to that of the PPARγ agonist (TROG) (Figure 5b). In particular, c-9,t-11-CLA significantly inibited IL-6 and INF-γ generation (by 34 ± 15%, p < 0.05 and by 37 ± 12%, p < 0.05, respectively) and the CLA blend inibited IL-6, TNF-α and INF-γ (by 65 ± 4%,p < 0.001; by 42 ± 17%, p < 0.05; by 49 ± 6%, p < 0.01, respectively). t-10,c-12-CLA also reduced IL-6, TNF-α and IL-12p70 (by 51 ± 7%,p < 0.01; by 40 ± 16%, p < 0.05 and by 38 ± 17%, p < 0.05, respectively) and TROG reduced generation of IL-6, TNF-α, INF-γ and IL12p70.Figure 5

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