Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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The Roles of CD137 Signaling in Atherosclerosis

  • Jung, In-Hyuk (Department of Life Sciences, Ewha Womans University) ;
  • Oh, Goo Taeg (Department of Life Sciences, Ewha Womans University)
  • Received : 2015.12.31
  • Accepted : 2016.04.12
  • Published : 2016.11.30
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Abstract

The tumor necrosis factor receptor superfamily (TNFRSF), which includes CD40, LIGHT, and OX40, plays important roles in the initiation and progression of cardiovascular diseases, involving atherosclerosis. CD137, a member of TNFRSF, is a well-known activation-induced T cell co-stimulatory molecule and has been reported to be expressed in human atherosclerotic plaque lesions, and plays pivotal roles in mediating disease processes. In this review, we focus on and summarize recent advances in mouse studies on the involvement of CD137 signaling in the pathogenesis and plaque stability of atherosclerosis, thereby highlighting a valuable therapeutic target in atherosclerosis.

Keywords

Acknowledgement

Supported by : National Research Foundation (NRF) of Korea

References

  1. Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis. Nat Med 2002;8:1218-26. https://doi.org/10.1038/nm1102-1218
  2. Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 2002;8:1211-7. https://doi.org/10.1038/nm1102-1211
  3. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011;3:204-12.
  4. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006;7:508-19.
  5. Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002;91:281-91. https://doi.org/10.1161/01.RES.0000029784.15893.10
  6. Stancel N, Chen CC, Ke LY, et al. Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis. Clin Chem 2016;62:320-7. https://doi.org/10.1373/clinchem.2015.243923
  7. Bjorkbacka H, Fredrikson GN, Nilsson J. Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis - a review of the experimental evidence. Atherosclerosis 2013;227:9-17. https://doi.org/10.1016/j.atherosclerosis.2012.10.074
  8. Clarke M, Bennett M. The emerging role of vascular smooth muscle cell apoptosis in atherosclerosis and plaque stability. Am J Nephrol 2006;26:531-5. https://doi.org/10.1159/000097815
  9. Tabas I, Tall A, Accili D. The impact of macrophage insulin resistance on advanced atherosclerotic plaque progression. Circ Res 2010;106:58-67. https://doi.org/10.1161/CIRCRESAHA.109.208488
  10. Lusis AJ. Atherosclerosis. Nature 2000;407:233-41. https://doi.org/10.1038/35025203
  11. Newby AC. Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc Med 2007;17:253-8. https://doi.org/10.1016/j.tcm.2007.09.001
  12. Vinay DS, Kwon BS. Immunotherapy of cancer with 4-1BB. Mol Cancer Ther 2012;11:1062-70. https://doi.org/10.1158/1535-7163.MCT-11-0677
  13. Zhang GB, Dong QM, Hou JQ, et al. Characterization and application of three novel monoclonal antibodies against human 4-1BB: distinct epitopes of human 4-1BB on lung tumor cells and immune cells. Tissue Antigens 2007;70:470-9. https://doi.org/10.1111/j.1399-0039.2007.00943.x
  14. Broll K, Richter G, Pauly S, Hofstaedter F, Schwarz H. CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am J Clin Pathol 2001;115:543-9. https://doi.org/10.1309/E343-KMYX-W3Y2-10KY
  15. Wan YL, Zheng SS, Zhao ZC, Li MW, Jia CK, Zhang H. Expression of co-stimulator 4-1BB molecule in hepatocellular carcinoma and adjacent non-tumor liver tissue, and its possible role in tumor immunity. World J Gastroenterol 2004;10:195-9. https://doi.org/10.3748/wjg.v10.i2.195
  16. Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol 2006;1:297-329. https://doi.org/10.1146/annurev.pathol.1.110304.100100
  17. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006;86:515-81. https://doi.org/10.1152/physrev.00024.2005
  18. Bodmer JL, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci 2002;27:19-26. https://doi.org/10.1016/S0968-0004(01)01995-8
  19. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001;104:487-501. https://doi.org/10.1016/S0092-8674(01)00237-9
  20. Robertson AK, Hansson GK. T cells in atherogenesis: for better or for worse? Arterioscler Thromb Vasc Biol 2006;26:2421-32. https://doi.org/10.1161/01.ATV.0000245830.29764.84
  21. Kwon B, Kim BS, Cho HR, Park JE, Kwon BS. Involvement of tumor necrosis factor receptor superfamily(TNFRSF) members in the pathogenesis of inflammatory diseases. Exp Mol Med 2003;35:8-16. https://doi.org/10.1038/emm.2003.2
  22. Lee SW, Park Y, Song A, Cheroutre H, Kwon BS, Croft M. Functional dichotomy between OX40 and 4-1BB in modulating effector CD8 T cell responses. J Immunol 2006;177:4464-72. https://doi.org/10.4049/jimmunol.177.7.4464
  23. Binder CJ, Hartvigsen K, Chang MK, et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest 2004;114:427-437. https://doi.org/10.1172/JCI200420479
  24. Chistiakov DA, Bobryshev YV, Orekhov AN. Macrophage-mediated cholesterol handling in atherosclerosis. J Cell Mol Med 2016;20:17-28. https://doi.org/10.1111/jcmm.12689
  25. Smith E, Prasad KM, Butcher M, et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010;121:1746-55. https://doi.org/10.1161/CIRCULATIONAHA.109.924886
  26. Butcher MJ, Gjurich BN, Phillips T, Galkina EV. The IL-17A/IL-17RA axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment. Circ Res 2012;110:675-87. https://doi.org/10.1161/CIRCRESAHA.111.261784
  27. Taleb S, Romain M, Ramkhelawon B, et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 2009;206:2067-77. https://doi.org/10.1084/jem.20090545
  28. Liao YH, Xia N, Zhou SF, et al. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol 2012;59:420-9. https://doi.org/10.1016/j.jacc.2011.10.863
  29. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775-87. https://doi.org/10.1016/j.cell.2008.05.009
  30. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 2008;9:239-44. https://doi.org/10.1038/ni1572
  31. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008;8:523-32. https://doi.org/10.1038/nri2343
  32. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-6. https://doi.org/10.1038/ni904
  33. Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol 2007;8:457-62. https://doi.org/10.1038/ni1455
  34. Foks AC, Litchman AH, Kuiper J. Treating atherosclerosis with regulatory T cells. Arterioscler Thromb Vasc Biol 2015;35:280-7. https://doi.org/10.1161/ATVBAHA.114.303568
  35. Mor A, Planer D, Luboshits G, et al. Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis. Arterioscler Thromb Vasc Biol 2007;27:893-900. https://doi.org/10.1161/01.ATV.0000259365.31469.89
  36. Wang Z, Mao S, Zhan Z, Yu K, He C, Wang C. Effect of hyperlipidemia on Foxp3 expression in apolipoprotein E-knockout mice. J Cardiovasc Med (Hagerstown) 2014;15:273-9. https://doi.org/10.2459/JCM.0b013e3283641b9c
  37. Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006;12:178-80. https://doi.org/10.1038/nm1343
  38. Gotsman I, Grabie N, Gupta R, et al. Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 2006;114:2047-55. https://doi.org/10.1161/CIRCULATIONAHA.106.633263
  39. Mallat Z, Gojova A, Marchiol-Fournigault C, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001;89:930-4. https://doi.org/10.1161/hh2201.099415
  40. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8. https://doi.org/10.1038/nature04753
  41. Lin J, Li M, Wang Z, He S, Ma X, Li D. The role of CD4+CD25+ regulatory T cells in macrophage-derived foam-cell formation. J Lipid Res 2010;51:1208-17. https://doi.org/10.1194/jlr.D000497
  42. Maganto-Garcia E, Bu DX, Tarrio ML, et al. Foxp3+-inducible regulatory T cells suppress endothelial activation and leukocyte recruitment. J Immunol 2011;187:3521-9. https://doi.org/10.4049/jimmunol.1003947
  43. Gotsman I, Sharpe AH, Lichtman AH. T-cell costimulation and coinhibition in atherosclerosis. Circ Res 2008;103:1220-31. https://doi.org/10.1161/CIRCRESAHA.108.182428
  44. Smeets E, Meiler S, Lutgens E. Lymphocytic tumor necrosis factor receptor superfamily co-stimulatory molecules in the pathogenesis of atherosclerosis. Curr Opin Lipidol 2013;24:518-24. https://doi.org/10.1097/MOL.0000000000000025
  45. Michallet MC, Rota G, Maslowski K, Guarda G. Innate receptors for adaptive immunity. Curr Opin Microbiol 2013;16:296-302. https://doi.org/10.1016/j.mib.2013.04.003
  46. Reynolds JM, Dong C. Toll-like receptor regulation of effector T lymphocyte function. Trends Immunol 2013;34:511-9. https://doi.org/10.1016/j.it.2013.06.003
  47. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol 2015;94:193-205. https://doi.org/10.1111/ejh.12427
  48. Lutgens E, Lievens D, Beckers L, et al. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med 2010;207:391-404. https://doi.org/10.1084/jem.20091293
  49. van Wanrooij EJ, van Puijvelde GH, de Vos P, Yagita H, van Berkel TJ, Kuiper J. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) pathway attenuates atherogenesis in low-density lipoprotein receptordeficient mice. Arterioscler Thromb Vasc Biol 2007;27:204-10. https://doi.org/10.1161/01.ATV.0000251007.07648.81
  50. Olofsson PS, Soderstrom LA, Wagsater D, et al. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 2008;117:1292-301. https://doi.org/10.1161/CIRCULATIONAHA.107.699173
  51. Jeon HJ, Choi JH, Jung IH, et al. CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation 2010;121:1124-33. https://doi.org/10.1161/CIRCULATIONAHA.109.882704
  52. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003;3:609-20. https://doi.org/10.1038/nri1148
  53. Makkouk A, Chester C, Kohrt HE. Rationale for anti-CD137 cancer immunotherapy. Eur J Cancer 2016;54:112-9. https://doi.org/10.1016/j.ejca.2015.09.026
  54. Vinay DS, Kwon BS. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Rep 2014;47:122-9. https://doi.org/10.5483/BMBRep.2014.47.3.283
  55. Kwon BS, Hurtado JC, Lee ZH, et al. Vinay DS. Immune responses in 4-1BB (CD137)-deficient mice. J Immunol 2002;168:5483-90. https://doi.org/10.4049/jimmunol.168.11.5483
  56. Lee SW, Vella AT, Kwon BS, Croft M. Enhanced CD4 T cell responsiveness in the absence of 4-1BB. J Immunol 2005;174:6803-8. https://doi.org/10.4049/jimmunol.174.11.6803
  57. Vinay DS, Choi BK, Bae JS, Kim WY, Gebhardt BM, Kwon BS. CD137-deficient mice have reduced NK/NKT cell numbers and function, are resistant to lipopolysaccharide-induced shock syndromes, and have lower IL-4 responses. J Immunol 2004;173:4218-29. https://doi.org/10.4049/jimmunol.173.6.4218
  58. Choi BK, Kim YH, Kwon PM, et al. 4-1BB functions as a survival factor in dendritic cells. J Immunol 2009;182:4107-15. https://doi.org/10.4049/jimmunol.0800459
  59. Lee SW, Park Y, Eun SY, Madireddi S, Cheroutre H, Croft M. Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase. J Immunol 2012;189:2697-701. https://doi.org/10.4049/jimmunol.1201248
  60. Yan J, Gong J, Liu P, Wnag C, Chen G. Positive correlation between CD137 expression and complex stenosis morphology in patients with acute coronary syndromes. Clin Chim Acta 2011;412:993-8. https://doi.org/10.1016/j.cca.2011.02.038
  61. Dongming L, Zuxun L, Liangjie X, Biao W, Ping Y. Enhanced levels of soluble and membrane-bound CD137 levels in patients with acute coronary syndromes. Clin Chim Acta 2010;411:406-10. https://doi.org/10.1016/j.cca.2009.12.011
  62. Yan J, Wang C, Wang Z, Yuan W. The effect of CD137-CD137 ligand interaction on phospholipase C signaling pathway in human endothelial cells. Chem Biol Interact 2013;206:256-61. https://doi.org/10.1016/j.cbi.2013.09.014
  63. Yu Y, He Y, Yang TT, et al. Elevated plasma levels and monocyteassociated expression of CD137 ligand in patients with acute atherothrombotic stroke. Eur Rev Med Pharmacol Sci 2014;18:1525-32.
  64. Yan J, Wang C, Chen R, Yang H. Clinical implications of elevated serum soluble CD137 levels in patients with acute coronary syndrome. Clinics (Sao Paulo) 2013;68:193-8. https://doi.org/10.6061/clinics/2013(02)OA12
  65. Li Y, Yan J, Wu C, Wang Z, Yuan W, Wang D. CD137-CD137L interaction regulates atherosclerosis via cyclophilin A in apolipoprotein E-deficient mice. PLoS One 2014;9:e88563. https://doi.org/10.1371/journal.pone.0088563
  66. Silvestre-Roig C, de Winther M, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ Res 2014;114:214-26. https://doi.org/10.1161/CIRCRESAHA.114.302355
  67. Choi ET, Collins ET, Marine LA, et al. Matrix metalloproteinase-9 modulation by resident arterial cells is responsible for injury-induced accelerated atherosclerotic plaque development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2005;25:1020-5. https://doi.org/10.1161/01.ATV.0000161275.82687.f6
  68. Kuzuya M, Nakamura K, Sasaki T, Cheng XW, Itohara S, Iguchi A. Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2006;26:1120-5. https://doi.org/10.1161/01.ATV.0000218496.60097.e0
  69. Mittal B, Mishra A, Srivastava A, Kumar S, Garg N. Matrix metalloproteinases in coronary artery disease. Adv Clin Chem 2014;64:1-72.
  70. Gough PJ, Gomez IG, Wille PT, Raines EW. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J Clin Invest 2006;116:59-69.
  71. Chen Y, Aratani Y, Osawa T, Fukuyama N, Tsuji C, Nakazawa H. Activation of inducible nitric oxide synthase increases MMP-2 and MMP-9 levels in ApoE-knockout mice. Tokai J Exp Clin Med 2008;33:28-34.
  72. Wei DH, Jia XY, Liu YH, et al. Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: potential role in atherosclerosis. Int J Mol Med 2013;31:400-6. https://doi.org/10.3892/ijmm.2012.1201
  73. Kitamoto S, Sukhova GK, Sun J, et al. Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptorknockout mice. Circulation 2007;115:2065-75. https://doi.org/10.1161/CIRCULATIONAHA.107.688523
  74. Sukhova GK, Zhang Y, Pan JH, et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2003;111:897-906. https://doi.org/10.1172/JCI200314915
  75. Guo J, Bot I, de Nooijer R, et al. Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in lowdensity lipoprotein receptor deficient mice. Cardiovasc Res 2009;81:278-85.
  76. Jaffer FA, Kim DE, Quinti L, et al. Optical visualization of cathepsin K activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. Circulation 2007;115:2292-8. https://doi.org/10.1161/CIRCULATIONAHA.106.660340
  77. Samokhin AO, Wong A, Saftig P, Bromme D. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis 2008;200:58-68. https://doi.org/10.1016/j.atherosclerosis.2007.12.047
  78. Levick SP, Goldspink PH. Could interferon-gamma be a therapeutic target for treating heart failure? Heart Fail Rev 2014;19:227-36. https://doi.org/10.1007/s10741-013-9393-8
  79. Harvey EJ, Ramji DP. Interferon-gamma and atherosclerosis: pro- or anti-atherogenic? Cardiovasc Res 2005;67:11-20. https://doi.org/10.1016/j.cardiores.2005.04.019
  80. Smith MA, Moylan JS, Smith JD, Li W, Reid MB. IFN-gamma does not mimic the catabolic effects of TNF-alpha. Am J Physiol Cell Physiol 2007;293:C1947-52. https://doi.org/10.1152/ajpcell.00269.2007
  81. Scott RA, Panitch A. Decorin mimic regulates platelet-derived growth factor and interferon-$\gamma$ stimulation of vascular smooth muscle cells. Biomacromolecules 2014;15:2090-103. https://doi.org/10.1021/bm500224f
  82. Dollery CM, Libby P. Atherosclerosis and proteinase activation. Cardiovasc Res 2006;69:625-35. https://doi.org/10.1016/j.cardiores.2005.11.003
  83. Yan J, Chen G, Gong J, Wang C, Du R. Upregulation of OX40-OX40 ligand system on T lymphocytes in patients with acute coronary syndromes. J Cardiovasc Pharmacol 2009;54:451-5. https://doi.org/10.1097/FJC.0b013e3181be7578
  84. Liu DM, Yan JC, Wang CP, et al. The clinical implications of increased OX40 ligand expression in patients with acute coronary syndrome. Clin Chim Acta 2008;397:22-6. https://doi.org/10.1016/j.cca.2008.07.003
  85. Lee WH, Kim SH, Lee Y, et al. Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. Arterioscler Thromb Vasc Biol 2010;21:2004-10.
  86. Kim SH, Lee WH, Kwon BS, Oh GT, Choi YH, Park JE. Tumor necrosis factor receptor superfamily 12 may destabilize atherosclerotic plaques by inducing matrix metalloproteinases. Jpn Circ J 2001;65:136-8. https://doi.org/10.1253/jcj.65.136
  87. Jung IH, Choi JH, Jin J, et al. CD137-inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice. FASEB J 2014;28:4779-91. https://doi.org/10.1096/fj.14-253732
  88. Choi JH, Cheong C, Dandamudi DB, et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity 2011;35:819-31. https://doi.org/10.1016/j.immuni.2011.09.014
  89. Pauly S, Broll K, Wittmann M, Giegerich G, Schwarz H. CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers. J Leukoc Biol 2002;72:35-42.
  90. Choi BK, Kim YH, Kwon PM, et al. 4-1BB functions as a survival factor in dendritic cells. J Immunol 2009;182:4107-15. https://doi.org/10.4049/jimmunol.0800459
  91. Kuang Y, Weng X, Liu X, Zhu H, Chen Z, Chen H. Effects of 4-1BB signaling on the biological function of murine dendritic cells. Oncol Lett 2011;3:477-81.
  92. Lee SW, Park Y, Eun SY, Madireddi S, Cheroutre H, Croft M. Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase. J Immunol 2012;189:2697-701. https://doi.org/10.4049/jimmunol.1201248

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