RSS-Feed abonnieren
DOI: 10.1160/TH11-05-0342
Current views on the functions of interleukin-17A-producing cells in atherosclerosis
Publikationsverlauf
Received:
20. Mai 2011
Accepted after minor revision:
08. August 2011
Publikationsdatum:
23. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201105/lookinside/thumbnails/10-1160-th11-05-0342-1.jpg)
Summary
Multiple components of the immune response are involved in the initiation, progression and persistence of atherosclerosis. Interleukin (IL)-17A is produced by a broad variety of leukocytes and plays an important role in host defense. IL-17A is also involved in the pathology of several autoimmune diseases mainly via the regulation of chemokine expression and leukocyte migration to the site of inflammation. There is an increasing body of evidence indicating an association between elevated levels of IL-17A and cardiovascular diseases. Interestingly, this IL- 17A-dependent response occurs in parallel with the Th1-dominant immune response during atherogenesis. To date, the precise role of IL-17A+ cells in atherosclerosis is controversial. Several studies have suggested a pro-atherogenic role of IL-17A via the regulation of aortic macrophage numbers, Th1-related cytokines and aortic chemokine expression. However, two studies recently described anti-inflammatory effects of IL-17A on mouse plaque burden via possible regulation of aortic VCAM-1 expression and T cell content. Furthermore, an initial study using IL-17A-deficient mice demonstrated that IL-17A affects the immune composition and inflammatory phenotype of the aortic wall; however, no effects were observed on atherosclerosis. Further studies are necessary to fully address the role of IL-17A and other IL-17 family members in atherosclerosis.
-
References
- 1 Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol 2009; 27: 165-197.
- 2 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204-212.
- 3 Erbel C, Chen L, Bea F. et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol 2009; 183: 8167-8175.
- 4 Smith E, Prasad KM, Butcher M. et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010; 121: 1746-1755.
- 5 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: 2067-2077.
- 6 Bettelli E, Korn T, Oukka M. et al. Induction and effector functions of T(H)17 cells. Nature 2008; 453: 1051-1057.
- 7 Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 2010; 10: 479-489.
- 8 Roger VL, Go AS, Lloyd-Jones DM. et al. Executive Summary: Heart Disease and Stroke Statistics--2011 Update: A Report From the American Heart Association. Circulation 2011; 123: 459-463.
- 9 Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989; 135: 169-175.
- 10 Jonasson L, Holm J, Skalli O. et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6: 131-138.
- 11 Galkina E, Kadl A, Sanders J. et al. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med 2006; 203: 1273-1282.
- 12 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6: 508-519.
- 13 Bobryshev YV, Lord RS. Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of Vascular Dendritic Cells in athero-resistant and athero-prone areas of the normal aorta. Arch Histol Cytol 1995; 58: 307-322.
- 14 Choi JH, Do Y, Cheong G, Koh H, Boscardin SB, Oh YS, Bozzacco L, Trumpfheller C, Park CG, Steinman RM. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med 2009; 206: 497-505.
- 15 Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med 2006; 203: 2073-2083.
- 16 Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res 2010; 106: 383-390.
- 17 Rossmann A, Henderson B, Heidecker B, Seiler R, Fraedrich G, Singh M, Parson W, Keller M, Grubeck-Loebenstein B, Wick G. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire. Exp Gerontol 2008; 43: 229-237.
- 18 Paulsson G, Zhou X, Tornquist E, Hansson GK. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2000; 20: 10-17.
- 19 Stemme S, Faber B, Holm J. et al. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA 1995; 92: 3893-3897.
- 20 Steinberg D. The LDL modification hypothesis of atherogenesis: an update. J Lipid Res. 2009; 50 (Suppl) S376-S381.
- 21 Hermansson A, Ketelhuth DF, Strodthoff D. et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 2010; 207: 1081-1093.
- 22 Davenport P, Tipping PG. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 2003; 163: 1117-1125.
- 23 King VL, Szilvassy SJ, Daugherty A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice. Arterioscler Thromb Vasc Biol 2002; 22: 456-461.
- 24 Huber SA, Sakkinen P, David C. et al. T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 2001; 103: 2610-2616.
- 25 Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133: 775-787.
- 26 Taleb S, Tedgui A, Mallat Z. Regulatory T-cell immunity and its relevance to atherosclerosis. J Intern Med 2008; 263: 489-499.
- 27 Bettelli E, Korn T, Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 2007; 19: 652-657.
- 28 Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004; 21: 467-476.
- 29 Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 2009; 9: 556-567.
- 30 Iwakura Y, Ishigame H, Saijo S. et al. Functional specialization of interleukin-17 family members. Immunity 2011; 34: 149-162.
- 31 Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008; 28: 454-467.
- 32 Wright JF, Guo Y, Quazi A. et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J Biol Chem 2007; 282: 13447-13455.
- 33 Chang SH, Dong C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res 2007; 17: 435-440.
- 34 Hurst SD, Muchamuel T, Gorman DM. et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 2002; 169: 443-453.
- 35 Li H, Chen J, Huang A. et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci USA 2000; 97: 773-778.
- 36 Yamaguchi Y, Fujio K, Shoda H. et al. IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol 2007; 179: 7128-7136.
- 37 Maitra A, Shen F, Hanel W. et al. Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc Natl Acad Sci USA 2007; 104: 7506-7511.
- 38 Shen F, Li N, Gade P. et al. IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain. Sci Signal 2009; 2: ra8
- 39 Toy D, Kugler D, Wolfson M. et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol 2006; 177: 36-39.
- 40 Rickel EA, Siegel LA, Yoon BR. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol 2008; 181: 4299-4310.
- 41 Hirahara K, Ghoreschi K, Laurence A. et al. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev 2010; 21: 425-434.
- 42 Robertson AK, Rudling M, Zhou X. et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 2003; 112: 1342-1350.
- 43 Zhou L, Lopes JE, Chong MM. et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008; 453: 236-240.
- 44 Eid RE, Rao DA, Zhou J. et al. Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 2009; 119: 1424-1432.
- 45 Cheng X, Yu X, Ding YJ. et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008; 127: 89-97.
- 46 Ghoreschi K, Laurence A, Yang XP. et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 2010; 467: 967-971.
- 47 Ausiello CM, Fedele G, Palazzo R. et al. 60-kDa heat shock protein of Chlamydia pneumoniae promotes a T helper type 1 immune response through IL-12/IL-23 production in monocyte-derived dendritic cells. Microbes Infect 2006; 8: 714-720.
- 48 Langrish CL, Chen Y, Blumenschein WM. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233-240.
- 49 Mosorin M, Surcel HM, Laurila A. et al. Detection of Chlamydia pneumoniae-reactive T lymphocytes in human atherosclerotic plaques of carotid artery. Arterioscler Thromb Vasc Biol 2000; 20: 1061-1067.
- 50 Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med 2007; 4: 444-454.
- 51 Ivanov II, Atarashi K, Manel N. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139: 485-498.
- 52 Chen Y, Chou K, Fuchs E. et al. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 2002; 99: 14338-14343.
- 53 Kinugasa T, Sakaguchi T, Gu X. et al. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 2000; 118: 1001-1011.
- 54 Sutton CE, Lalor SJ, Sweeney CM. et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31: 331-341.
- 55 Kolls JK, Khader SA. The role of Th17 cytokines in primary mucosal immunity. Cytokine Growth Factor Rev 2010; 21: 443-448.
- 56 Ivanov II, McKenzie BS, Zhou L. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126: 1121-1133.
- 57 Wilson NJ, Boniface K, Chan JR. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8: 950-957.
- 58 Ye P, Rodriguez FH, Kanaly S. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 2001; 194: 519-527.
- 59 Chung DR, Kasper DL, Panzo RJ. et al. CD4+ T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism. J Immunol 2003; 170: 1958-1963.
- 60 Huo Y, Weber C, Forlow SB. et al. The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest 2001; 108: 1307-1314.
- 61 Jovanovic DV, Di Battista JA, Martel-Pelletier J. et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 1998; 160: 3513-3521.
- 62 Chen Y, Langrish CL, McKenzie B. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 2006; 116: 1317-1326.
- 63 Sutton C, Brereton C, Keogh B. et al. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 2006; 203: 1685-1691.
- 64 Siffrin V, Radbruch H, Glumm R. et al. In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 2010; 33: 424-436.
- 65 Haak S, Croxford AL, Kreymborg K. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 2009; 119: 61-69.
- 66 Feng T, Qin H, Wang L. et al. Th17 Cells Induce Colitis and Promote Th1 Cell Responses through IL-17 Induction of Innate IL-12 and IL-23 Production. J Immunol 2011; 186: 6313-6318.
- 67 Kamanaka M, Huber S, Zenewicz LA. et al. Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med 2011; 208: 1027-1040.
- 68 O'Connor Jr. W, Kamanaka M, Booth CJ. et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 2009; 10: 603-609.
- 69 Ogawa A, Andoh A, Araki Y. et al. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol 2004; 110: 55-62.
- 70 Annunziato F, Cosmi L, Santarlasci V. et al. Phenotypic and functional features of human Th17 cells. J Exp Med 2007; 204: 1849-1861.
- 71 Costa-Rodriguez EV, Rivino L, Geginat J. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007; 8: 639-646.
- 72 Lowes MA, Kikuchi T, Fuentes-Duculan J. et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 2008; 128: 1207-1211.
- 73 Nistala K, Moncrieffe H, Newton KR. et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum 2008; 58: 875-887.
- 74 Suryani S, Sutton I. An interferon-gamma-producing Th1 subset is the major source of IL-17 in experimental autoimmune encephalitis. J Neuroimmunol 2007; 183: 96-103.
- 75 Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009; 30: 646-655.
- 76 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: 235-238.
- 77 Voo KS, Wang YH, Santori FR. et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009; 106: 4793-4798.
- 78 Erbel C, Dengler TJ, Wangler S. et al. Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability. Basic Res Cardiol 2011; 106: 125-134.
- 79 Wang Z, Lee J, Zhang Y. et al. Increased Th17 cells in coronary artery disease are associated with neutrophilic inflammation. Scand Cardiovasc J 2011; 45: 54-61.
- 80 Zhao Z, Wu Y, Cheng M. et al. Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis 2011; 518: 518-524.
- 81 Gao Q, Jiang Y, Ma T. et al. A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice. J Immunol 2010; 185: 5820-5827.
- 82 van Es T, van Puijvelde GH, Ramos OH. et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun 2009; 388: 261-265.
- 83 Xie JJ, Wang J, Tang TT. et al. The Th17/Treg functional imbalance during atherogenesis in ApoE(-/-) mice. Cytokine 2010; 49: 185-193.
- 84 Madhur MS, Funt SA, Li L. et al. Role of Interleukin 17 in Inflammation, Atherosclerosis, and Vascular Function in Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol 2011; 31: 1565-1572.
- 85 Cheng X, Taleb S, Wang J. et al. Inhibition of IL-17A in atherosclerosis. Atherosclerosis 2011; 215: 471-474.
- 86 Patel S, Chung SH, White G. et al. The “atheroprotective” mediators apolipoproteinA-I and Foxp3 are over-abundant in unstable carotid plaques. Int J Cardiol 2010; 145: 183-187.