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

Journal of Inflammation

Orina Belton¹  Simone Marcone²  Kawthar Alghamdi¹  Monica de Gaetano¹ 

[1] School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Dublin, Ireland;School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland

关键词: Cholesterol efflux;    Scavenger receptors;    Foam cell formation;    Macrophage differentiation;    Atherosclerosis;    Conjugated linoleic acid;   

Others  :  1134146
DOI  :  10.1186/s12950-015-0060-9

 received in 2014-07-25, accepted in 2015-02-03,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 de Gaetano et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Chinetti-Gbaguidi G, Staels B: Macrophage polarization in metabolic disorders: functions and regulation. Curr Opin Lipidol 2011, 22(5):365-72.
• [2]Tabas I, Williams KJ, Boren J: Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007, 116(16):1832-44.
• [3]Falk E: Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006, 47(8 Suppl):C7-12.
• [4]de Gaetano M, Dempsey E, Marcone S, James WG, Belton O: Conjugated Linoleic Acid Targets beta2 Integrin Expression To Suppress Monocyte Adhesion. J Immunol 2013, 191(8):4326-36.
• [5]Tushinski RJ, Oliver IT, Guilbert LJ, Tynan PW, Warner JR, Stanley ER: Survival of mononuclear phagocytes depends on a lineage-specific growth factor that the differentiated cells selectively destroy. Cell 1982, 28(1):71-81.
• [6]Warren MK, Ralph P: Macrophage growth factor CSF-1 stimulates human monocyte production of interferon, tumor necrosis factor, and colony stimulating activity. J Immunol 1986, 137(7):2281-5.
• [7]Di Gregoli K, Johnson JL: Role of colony-stimulating factors in atherosclerosis. Curr Opin Lipidol 2012, 23(5):412-21.
• [8]Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y: Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways. Circ Res 2011, 108(8):985-95.
• [9]Jessup W, Gelissen IC, Gaus K, Kritharides L: Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages. Curr Opin Lipidol 2006, 17(3):247-57.
• [10]Kzhyshkowska J, Neyen C, Gordon S: Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 2012, 217(5):492-502.
• [11]Mosser DM, Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008, 8(12):958-69.
• [12]Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT: Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994, 90(2):775-8.
• [13]Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C: Innate immunity and monocyte-macrophage activation in atherosclerosis. J Inflamm (Lond) 2011, 8:9. BioMed Central Full Text
• [14]Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, et al.: PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007, 6(2):137-43.
• [15]Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, Nakagawara J, et al.: The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J Stroke Cerebrovasc Dis 2013, 22(7):910-8.
• [16]Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M, et al.: Macrophage plasticity in experimental atherosclerosis. PLoS One 2010, 5(1):e8852.
• [17]McCarthy C, Duffy MM, Mooney D, James WG, Griffin MD, Fitzgerald DJ, et al.: IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis. FASEB J 2012, 27(2):499-510.
• [18]Feig JE, Parathath S, Rong JX, Mick SL, Vengrenyuk Y, Grauer L, et al.: Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 2011, 123(9):989-98.
• [19]Banni S: Conjugated linoleic acid metabolism. Curr Opin Lipidol 2002, 13(3):261-6.
• [20]Kelley NS, Hubbard NE, Erickson KL: Conjugated linoleic acid isomers and cancer. J Nutr 2007, 137(12):2599-607.
• [21]Kritchevsky D: Antimutagenic and some other effects of conjugated linoleic acid. Br J Nutr 2000, 83(5):459-65.
• [22]Navarro V, Fernández-Quintela A, Churruca I, Portillo MP, et al.: The body fat-lowering effect of conjugated linoleic acid: a comparison between animal and human studies. J Physiol Biochem 2006, 62(2):137-47.
• [23]Wang YW, Jones PJ: Conjugated linoleic acid and obesity control: efficacy and mechanisms. Int J Obes Relat Metab Disord 2004, 28(8):941-55.
• [24]Reynolds CM, Roche HM: Conjugated linoleic acid and inflammatory cell signalling. Prostaglandins Leukot Essent Fatty Acids 2010, 82(4–6):199-204.
• [25]Toomey S, Harhen B, Roche HM, Fitzgerald D, Belton O, et al.: Profound resolution of early atherosclerosis with conjugated linoleic acid. Atherosclerosis 2006, 187(1):40-9.
• [26]Toomey S, Roche H, Fitzgerald D, Belton O, et al.: Regression of pre-established atherosclerosis in the apoE−/− mouse by conjugated linoleic acid. Biochem Soc Trans 2003, 31(Pt 5):1075-9.
• [27]Arbones-Mainar JM, Navarro MA, Guzmán MA, Arnal C, Surra JC, Acín S, et al.: Selective effect of conjugated linoleic acid isomers on atherosclerotic lesion development in apolipoprotein E knockout mice. Atherosclerosis 2006, 189(2):318-27.
• [28]Kritchevsky D, Tepper SA, Wright S, Czarnecki SK, Wilson TA, Nicolosi RJ: Conjugated linoleic acid isomer effects in atherosclerosis: growth and regression of lesions. Lipids 2004, 39(7):611-6.
• [29]McClelland S, Cox C, O'Connor R, de Gaetano M, McCarthy C, Cryan L, et al.: Conjugated linoleic acid suppresses the migratory and inflammatory phenotype of the monocyte/macrophage cell. Atherosclerosis 2010, 211(1):96-102.
• [30]Mooney D, McCarthy C, Belton O: Effects of conjugated linoleic acid isomers on monocyte, macrophage and foam cell phenotype in atherosclerosis. Prostaglandins Other Lipid Mediat 2012, 98(3–4):56-62.
• [31]McCarthy C, Lieggi NT, Barry D, Mooney D, de Gaetano M, James WG, et al.: Macrophage PPAR gamma Co-activator-1 alpha participates in repressing foam cell formation and atherosclerosis in response to conjugated linoleic acid. EMBO Mol Med 2013, 5(9):1443-57.
• [32]Ringseis R, Wen G, Saal D, Eder K: Conjugated linoleic acid isomers reduce cholesterol accumulation in acetylated LDL-induced mouse RAW264.7 macrophage-derived foam cells. Lipids 2008, 43(10):913-23.
• [33]Yu Y, Correll PH, Vanden Heuvel JP: Conjugated linoleic acid decreases production of pro-inflammatory products in macrophages: evidence for a PPAR gamma-dependent mechanism. Biochim Biophys Acta 2002, 1581(3):89-99.
• [34]Evans M, Brown J, McIntosh M: Isomer-specific effects of conjugated linoleic acid (CLA) on adiposity and lipid metabolism. J Nutr Biochem 2002, 13(9):508.
• [35]Lee Y, Thompson JT, de Lera AR, Vanden Heuvel JP: Isomer-specific effects of conjugated linoleic acid on gene expression in RAW 264.7. J Nutr Biochem 2009, 20(11):848-59. 859 e1-5
• [36]Lee Y, Thompson JT, Vanden Heuvel JP: 9E,11E-conjugated linoleic acid increases expression of the endogenous antiinflammatory factor, interleukin-1 receptor antagonist, in RAW 264.7 cells. J Nutr 2009, 139(10):1861-6.
• [37]Etzerodt A, Moestrup SK: CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal 2013, 18(17):2352-63.
• [38]Feinberg H, Park-Snyder S, Kolatkar AR, Heise CT, Taylor ME, Weis WI: Structure of a C-type carbohydrate recognition domain from the macrophage mannose receptor. J Biol Chem 2000, 275(28):21539-48.
• [39]Taylor ME, Bezouska K, Drickamer K: Contribution to ligand binding by multiple carbohydrate-recognition domains in the macrophage mannose receptor. J Biol Chem 1992, 267(3):1719-26.
• [40]Boytard L, Spear R, Chinetti-Gbaguidi G, Acosta-Martin AE, Vanhoutte J, Lamblin N, et al.: Role of proinflammatory CD68(+) mannose receptor(−) macrophages in peroxiredoxin-1 expression and in abdominal aortic aneurysms in humans. Arterioscler Thromb Vasc Biol 2013, 33(2):431-8.
• [41]Wolfs IM, Donners MM, de Winther MP: Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb Haemost 2011, 106(5):763-71.
• [42]Lee KN, Kritchevsky D, Pariza MW: Conjugated linoleic acid and atherosclerosis in rabbits. Atherosclerosis 1994, 108(1):19-25.
• [43]Kostogrys RB, Franczyk-Żarów M, Maślak E, Gajda M, Mateuszuk Ł, Chłopicki S: Effects of margarine supplemented with t10c12 and C9T11 CLA on atherosclerosis and steatosis in apoE/LDLR −/− mice. J Nutr Health Aging 2012, 16(5):482-90.
• [44]Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG, Leesnitzer LA, Belury MA: Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha. J Lipid Res 1999, 40(8):1426-33.
• [45]Stachowska E, Kijowski J, Dziedziejko V, Siennicka A, Chlubek D: Conjugated linoleic acid regulates phosphorylation of PPARgamma by modulation of ERK 1/2 and p38 signaling in human macrophages/fatty acid-laden macrophages. J Agric Food Chem 2011, 59(21):11846-52.
• [46]Fleetwood AJ, Dinh H, Cook AD, Hertzog PJ, Hamilton JA: GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J Leukoc Biol 2009, 86(2):411-21.
• [47]Sierra-Filardi E, Vega MA, Sánchez-Mateos P, Corbí AL, Puig-Kröger A: Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release. Immunobiology 2010, 215(9–10):788-95.
• [48]Estruch M, Bancells C, Beloki L, Sanchez-Quesada JL, Ordóñez-Llanos J, Benitez S: CD14 and TLR4 mediate cytokine release promoted by electronegative LDL in monocytes. Atherosclerosis 2013, 229(2):356-62.
• [49]Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, et al.: Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 2002, 277(51):49982-8.
• [50]van der Kooij MA, Morand OH, Kempen HJ, van Berkel TJ: Decrease in scavenger receptor expression in human monocyte-derived macrophages treated with granulocyte macrophage colony-stimulating factor. Arterioscler Thromb Vasc Biol 1996, 16(1):106-14.
• [51]Tall AR, Costet P, Wang N: Regulation and mechanisms of macrophage cholesterol efflux. J Clin Invest 2002, 110(7):899-904.
• [52]Dai Y, Su W, Ding Z, Wang X, Mercanti F, Chen M, et al.: Regulation of MSR-1 and CD36 in macrophages by LOX-1 mediated through PPAR-gamma. Biochem Biophys Res Commun 2013, 431(3):496-500.
• [53]Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM: PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001, 7(1):48-52.
• [54]Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al.: A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 2001, 7(1):161-71.
• [55]Panzenboeck U, Kratzer I, Sovic A, Wintersperger A, Bernhart E, Hammer A, et al.: Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells. Int J Biochem Cell Biol 2006, 38(8):1314-29.
• [56]Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998, 93(2):229-40.
• [57]Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998, 93(2):241-52.
• [58]Lang R, Rutschman RL, Greaves DR, Murray PJ: Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter. J Immunol 2002, 168(7):3402-11.
• [59]Skrzeczynska-Moncznik J, Bzowska M, Loseke S, Grage-Griebenow E, Zembala M, Pryjma J: Peripheral blood CD14high CD16+ monocytes are main producers of IL-10. Scand J Immunol 2008, 67(2):152-9.
• [60]Walcher D, Kümmel A, Kehrle B, Bach H, Grüb M, Durst R, et al.: LXR activation reduces proinflammatory cytokine expression in human CD4-positive lymphocytes. Arterioscler Thromb Vasc Biol 2006, 26(5):1022-8.
• [61]Li CC, Hou YC, Yeh CL, Yeh SL: Effects of eicosapentaenoic acid and docosahexaenoic acid on prostate cancer cell migration and invasion induced by tumor-associated macrophages. PLoS One 2014, 9(6):e99630.
• [62]Grewal T, Priceputu E, Davignon J, Bernier L: Identification of a gamma-interferon-responsive element in the promoter of the human macrophage scavenger receptor A gene. Arterioscler Thromb Vasc Biol 2001, 21(5):825-31.
• [63]Panousis CG, Zuckerman SH: Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol 2000, 20(6):1565-71.
• [64]Reiss AB, Patel CA, Rahman MM, Chan ES, Hasneen K, Montesinos MC, et al.: Interferon-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages. Med Sci Monit 2004, 10(11):BR420-5.