Anti eotaxin-2 antibodies attenuate the initiation and progression of experimental atherosclerosis


Background: The chemokine eotaxin-2 is a potent chemoattractant for inflammatory cells, the predominants of which are eosinophils. Human and murine atherosclerotic plaques are known to exhibit inflammatory phenotypes where a complex interaction of cytokine and chemokines plays a role. We tested the hypothesis that eotaxin-2 (eo-2) plays a causative role in the initiation and progression of experimental atherosclerosis. Methods and Results: Sera collected from atherosclerotic ApoE knockout (KO) mice, exhibited significantly higher levels of eo-2 compared to sera collected from their background age matched C57BL/6 litters by ELISA. Moreover, levels of eo-2 were higher in old atherosclerotic ApoE KO mice than in young animals. Similarly, the expression level of the eo-2 receptor, CCR3, was increased in splenocytes of old ApoE compared to the young littermates. Administration of polyclonal blocking antibodies to eotaxin-2 resulted in a significant reduction of early atherosclerotic plaques in ApoE KO mice whereas prolonged treatment of mice with advanced plaques led to atheroma stabilization. A monoclonal antibody (D8) prepared against eo-2 attenuated adhesion of lymphocytes to fibronectin and potently inhibited their migration towards VEGF. Monoclonal blocking antibodies to eo-2 also significantly reduced atherosclerotic plaques in ApoE KO mice. Conclusion: Eo-2 serum levels are elevated in sera of ApoE KO mice with experimental atherosclerosis and its blockade is associated with reduced fatty streak accumulation and increased plaque stabilization.

Share and Cite:

Mor, A. , Afek, A. , Entin-Meer, M. , Keren, G. and George, J. (2013) Anti eotaxin-2 antibodies attenuate the initiation and progression of experimental atherosclerosis. World Journal of Cardiovascular Diseases, 3, 339-346. doi: 10.4236/wjcd.2013.34054.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Jose, P.J., Griffiths-Johnson, D.A., Collins, P.D., Walsh, D.T., Moqbel, R., Totty, N.F., Truong, O., Hsuan, J.J. and Williams, T.J. (1994) Eotaxin: A potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. The Journal of Experimental Medicine, 179, 881-887. doi:10.1084/jem.179.3.881
[2] Kitaura, M., Nakajima, T., Imai, T., Harada, S., Combadiere, C., Tiffany, H.L., Murphy, P.M. and Yoshie, O. (1996) Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. The Journal of Biological Chemistry, 271, 7725-7730. doi:10.1074/jbc.271.13.7725
[3] Ponath, P.D., Qin, S., Ringler, D.J., Clark-Lewis, I., Wang, J., Kassam, N., Smith, H., Shi, X., Gonzalo, J.A., Newman, W., Gutierrez-Ramos, J.C. and Mackay, C.R. (1996) Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. Journal of Clinical Investigation, 97, 604612. doi:10.1172/JCI118456
[4] Pease, J.E. (2006) Asthma, allergy and chemokines. Current Drug Targets, 7, 3-12. doi:10.2174/138945006775270204
[5] Berger, O., Gan, X., Gujuluva, C., Burns, A.R., Sulur, G., Stins, M., Way, D., Witte, M., Weinand, M., Said, J., Kim, K.S., Taub, D., Graves, M.C. and Fiala, M. (1999) CXC and CC chemokine receptors on coronary and brain endothelia. Molecular Medicine, 5, 795-805.
[6] Salcedo, R., Resaum J.H., Halversonm D., Hudsonm E.A., Dambach, M., Powell, D., Wasserman, K. and Oppenheim, J.J. (2000) Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells. The FASEB Journal, 14, 2055-2064. doi:10.1096/fj.99-0963com
[7] Romagnani, P., Annunziato, F., Lasagni, L., Lazzeri, E., Beltrame, C., Francalanci, M., Uguccioni, M., Galli, G., Cosmi, L., Maurenzig, L., Baggiolini, M., Maggi, E., Romagnani, S. and Serio, M. (2001) Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. Journal of Clinical Investigation, 107, 53-63. doi:10.1172/JCI9775
[8] Salcedo, R., Young, H.A., Ponce, M.L., Ward, J.M., Kleinman, H.K., Murphy, W.J. and Oppenheim, J.J. (2001) Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. The Journal of Immunology, 166, 7571-7578.
[9] Cheng, S.S., Lukacs, N.W. and Kunkel, S.L. (2002) Eotaxin/CCL11 suppresses IL-8/CXCL8 secretion from human dermal microvascular endothelial cells. The Journal of Immunology, 168, 2887-2894.
[10] Agrawal, L., Maxwell, C.R., Peters, P.J., Clapham, P.R., Liu, S.M., Mackay, C.R. and Strayer, D.S. (2009) Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: Roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia. Journal of General Virology, 90, 710-722. doi:10.1099/vir.0.006205-0
[11] Hansson, G.K. (2005) Inflammation, atherosclerosis, and coronary artery disease. The New England Journal of Medicine, 352, 1685-1695. doi:10.1056/NEJMra043430
[12] Sun, J., Sukhova, G.K., Wolters, P.J., Yang, M., Kitamoto, S., Libby, P., MacFarlane, L.A., Mallen-St Clair, J. and Shi, G.P. (2007) Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nature Medicine, 13, 719-724. doi:10.1038/nm1601
[13] Kodali, R., Hajjou, M., Berman, A.B., Bansal, M.B., Zhang, S., Pan, J.J. and Schecter, A.D. (2006) Chemokines induce matrix metalloproteinase-2 through activation of epidermal growth factor receptor in arterial smooth muscle cells. Cardiovascular Research, 69, 706-715. doi:10.1016/j.cardiores.2005.09.012
[14] Sheikine, Y., Olsen, B., Gharizadeh, B., Jatta, K., Tornvall, P. and Ghaderi, M. (2006) Influence of eotaxin 67G>A polymorphism on plasma eotaxin concentrations in myocardial infarction survivors and healthy controls. Atherosclerosis, 189, 458-463. doi:10.1016/j.atherosclerosis.2006.01.003
[15] Economou, E., Tousoulis, D., Katinioti, A., Stefanadis, C., Trikas, A., Pitsavos, C., Tentolouris, C., Toutouza, M.G. and Toutouzas, P. (2001) Chemokines in patients with ischaemic heart disease and the effect of coronary angioplasty. International Journal of Cardiology, 80, 55-60. doi:10.1016/S0167-5273(01)00454-5
[16] Emanuele, E., Falcone, C., D’Angelo, A., Minoretti, P., Buzzi, M.P., Bertona, M. and Geroldi, D. (2006) Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease. Atherosclerosis, 186, 140-145. doi:10.1016/j.atherosclerosis.2005.07.002
[17] Ardigo, D., Assimes, T.L., Fortmann, S.P., Go, A.S., Hlatky, M., Hytopoulos, E., Iribarren, C., Tsao, P.S., Tabibiazar, R., Quertermous, T. and ADVANCE Investigators (2007) Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease. Physiological Genomics, 31, 402-409.
[18] Sheikine, Y.A. and Hansson, G.K. (2006) Chemokines as potential therapeutic targets in atherosclerosis. Current Drug Targets, 7, 13-27. doi:10.2174/138945006775270240
[19] Ablin, J.N., Entin-Meer, M., Aloush, V., Oren, S., Elkayam, O., George, J. and Barshack, I. (2010) Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis. Clinical & Experimental Immunology, 161, 376-283. doi:10.1111/j.1365-2249.2010.04172.x
[20] Weber, C., Zernecke, A. and Libby, P. (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: Lessons from mouse models. Nature Reviews Immunology, 8, 802-815. doi:10.1038/nri2415
[21] Bot, I., de Jager, S.C., Zernecke, A., Lindstedt, K.A., van Berkel, T.J., Weber, C. and Biessen, E.A. (2007) Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation, 115, 2516-2525. doi:10.1161/01.ATV.14.9.1480
[22] Haley, K.J., Lilly, C.M., Yang, J.H., Feng, Y., Kennedy, S.P., Turi, T.G., Thompson, J.F., Sukhova, G.H., Libby, P. and Lee, R.T. (2000) Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: Using genomic technology to identify a potential novel pathway of vascular inflammation. Circulation, 102, 2185-2189. doi:10.1161/01.CIR.102.18.2185
[23] Kovanen, P.T. (2007) Mast cells: Multipotent local effector cells in atherothrombosis. Immunological Reviews, 217, 105-122. doi:10.1111/j.1600-065X.2007.00515.x
[24] Boring, L., Gosling, J., Cleary, M. and Charo, I.F. (1998) Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature, 394, 894-897. doi:10.1038/29788
[25] Hillyer, P., Mordelet, E., Flynn, G. and Male, D. (2003) Chemokines, chemokine receptors and adhesion molecules on different human endothelia: Discriminating the tissue-specific functions that affect leucocyte migration. Clinical & Experimental Immunology, 134, 431-441. doi:10.1111/j.1365-2249.2003.02323.x

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.