An inflammatory link in atherosclerosis and obesity

Summary

Atherosclerosis and obesity-induced metabolic dysfunction are lipid-driven inflammatory pathologies responsible for a major part of cardiovascular complications. Immune cell activation as well as interactions between the different immune cells is dependent on and controlled by a variety of co-stimulatory signals. These co-stimulatory signals can either aggravate or ameliorate the disease depending on the stage of the disease, the cell-types involved and the signal transduction cascades initiated. This review focuses on the diverse roles of the most established co-stimulatory molecules of the B7 and Tumor Necrosis Factor Receptor (TNFR) families, ie the CD28/CTLA4-CD80/CD86 and CD40L/CD40 dyads in the pathogenesis of atherosclerosis and obesity. In addition, we will explore their potential as therapeutic targets in both atherosclerosis and obesity.

Zusammenfassung

Atheroskleroseund Adipositas-induzierte metabolische Dysfunktionen sind lipid-assoziierte, inflammatorische Pathologien, welche für einen großen Teil kardiovaskulärer Komplikationen verantwortlich sind. Die Aktivierung von Immunzellen sowie die Kommunikation verschiedener Immunzellen untereinander sind von einer Vielzahl kostimulatorischer Signale abhängig. Diese kostimulatorischen Signale können den Krankheitsverlauf entweder aggravieren oder verbessern, jeweils in Abhängigkeit von dem Stadium der Erkrankung und den Zelltypen, die involviert sind sowie in Abhängigkeit der Signalkaskaden, welche aktiviert werden. Der folgende Review-Artikel hat die diversen Rollen der bekanntesten Vertreter kostimulatorischer Moleküle der B7 und TumornekrosefaktorRezeptor-Familie, z. B. die CD28/CTLA4-CD80/CD86-Interaktionen und die CD40L/ CD40-Interaktion in der Pathogenese von Atherosklerose und Adipositas zum Schwerpunkt. Darüber hinaus diskutieren wir das Potential kostimulatorischer Signalwege als therapeutisches Ziel in den beiden Krankheitsbildern Atherosklerose und Adipositas.

Keywords

Atherosclerosis - obesity - co-stimulation

Schlüsselwörter

Atherosklerose - Adipositas - Kostimulation

• References

• 1 Murray CJL, Vos T, Lozano R. et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2197-1223.
• 2 Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 2013; 38: 1092-1104.
• 3 Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012; 18: 363-374.
• 4 Legein B, Temmerman L, Biessen EAL. et al. Inflammation and immune system interactions in atherosclerosis. Cell Mol Life Sci 2013; 70: 3847-3869.
• 5 Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415-445.
• 6 Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 2009; 09: 271-285.
• 7 Leitner J, Grabmeier-Pfistershammer K, Steinberger P. Receptors and ligands implicated in human T cell costimulatory processes. Immunol Lett 2010; 128: 89-97.
• 8 Liu Y, Janeway CA. Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc Natl Acad Sci USA 1992; 89: 3845-3849.
• 9 Ding L, Shevach EM. Activation of CD4+ T cells by delivery of the B7 costimulatory signal on bystander antigen-presenting cells (trans-costimulation). Eur J Immunol 1994; 24: 859-866.
• 10 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: 518-524.
• 11 Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation - tipping the balance in atherosclerosis?. Thromb Haemost 2011; 106: 804-813.
• 12 Seijkens T, Kusters P, Chatzigeorgiou A. et al. Immune cell crosstalk in obesity: a key role for costimulation?. Diabetes 2014; 63: 3982-3991.
• 13 Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002; 02: 116-126.
• 14 Dopheide JF, Sester U, Schlitt A. et al. Monocytederived dendritic cells of patients with coronary artery disease show an increased expression of costimulatory molecules CD40, CD80 and CD86 in vitro. Coron Artery Dis 2007; 18: 523-531.
• 15 Mantani PT, Ljungcrantz I, Andersson L. et al. Circulating CD40+ and CD86+ B cell subsets demonstrate opposing associations with risk of stroke. Arterioscler Thromb Vasc Biol 2014; 34: 211-218.
• 16 Müller A, Mu L, Meletta R. et al. Towards non-invasive imaging of vulnerable atherosclerotic plaques by targeting co-stimulatory molecules. Int J Cardiol 2014; 174: 503-515.
• 17 de Boer OJ, Hirsch F, van der Wal AC. et al. Costimulatory molecules in human atherosclerotic plaques: an indication of antigen specific T lymphocyte activation. Atherosclerosis 1997; 133: 227-234.
• 18 Huxley P, Sutton DH, Debnam P. et al. High-affinity small molecule inhibitors of T cell costimulation: compounds for immunotherapy. Chem Biol 2004; 11: 1651-1658.
• 19 Doesch AO, Zhao L, Gleissner CA. et al. Inhibition of B7-1 (CD80) by RhuDex® reduces lipopolysaccharide-mediated inflammation in human atherosclerotic lesions. Drug Des Devel Ther 2014; 08: 447-457.
• 20 Buono C, Pang H, Uchida Y. et al. B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 2004; 109: 2009-2015.
• 21 Furukawa Y, Mandelbrot DA, Libby P. et al. Association of B7-1 co-stimulation with the development of graft arterial disease. Studies using mice lacking B7-1, B7-2, or B7-1/B7-2. Am J Pathol 2000; 157: 473-484.
• 22 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
• 23 Ewing MM, Karper JC, Abdul S. et al. T-cell costimulation by CD28-CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development. Int J Cardiol 2013; 168: 1965-1974.
• 24 Ma K, Lv S, Liu B. et al. CTLA4-IgG ameliorates homocysteine-accelerated atherosclerosis by inhibiting T-cell overactivation in apoE(-/-) mice. Cardiovasc Res 2013; 97: 349-359.
• 25 Zhong J, Rao X, Braunstein Z. et al. T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes 2014; 63: 1289-1302.
• 26 Chatzigeorgiou A, Chung K-J, Garcia-Martin R. et al. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology 2014; 60: 1196-1210.
• 27 Zeng M, Guinet E, Nouri-Shirazi M. B7-1 and B7-2 differentially control peripheral homeostasis of CD4(+)CD25(+)Foxp3(+) regulatory T cells. Transpl Immunol 2009; 20: 171-179.
• 28 Fujii M, Inoguchi T, Batchuluun B. et al. CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues. Biochem Biophys Res Commun 2013; 438: 103-109.
• 29 Lievens D, Eijgelaar WJ, Biessen EAL. et al. The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost 2009; 102: 206-214.
• 30 Engel D, Seijkens T, Poggi M. et al. The immunobiology of CD154-CD40-TRAF interactions in atherosclerosis. Semin Immunol 2009; 21: 308-312.
• 31 Grewal IS, Flavell RA. CD40 and CD154 in cellmediated immunity. Annu Rev Immunol 1998; 16: 111-135.
• 32 Lutgens E, Daemen MJAP. CD40-CD40L interactions in atherosclerosis. Trends Cardiovasc Med 2002; 12: 27-32.
• 33 Schönbeck U, Libby P. CD40 signaling and plaque instability. Circ Res 2001; 89: 1092-1103.
• 34 Garlichs CD, John S, Schmeisser A. et al. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation 2001; 104: 2395-2400.
• 35 Kopp CW, Steiner S, Nasel C. et al. Abciximab reduces monocyte tissue factor in carotid angioplasty and stenting. Stroke 2003; 34: 2560-2567.
• 36 Sanguigni V, Ferro D, Pignatelli P. et al. CD40 ligand enhances monocyte tissue factor expression and thrombin generation via oxidative stress in patients with hypercholesterolemia. J Am Coll Cardiol 2005; 45: 35-42.
• 37 Cipollone F, Chiarelli F, Davì G. et al. Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control. Diabetologia 2005; 48: 1216-1224.
• 38 Cipollone F, Ferri C, Desideri G. et al. Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty. Circulation 2003; 108: 2776-2782.
• 39 Heeschen C, Dimmeler S, Hamm CW. et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 1104-1111.
• 40 Wang C, Yan J, Yang P. et al. The relationship between CD40 gene polymorphism and unstable coronary atherosclerotic plaques. Clin Cardiol 2010; 33: E55-E60.
• 41 Lutgens E, Gorelik L, Daemen MJ. et al. Requirement for CD154 in the progression of atherosclerosis. Nat Med 1999; 05: 1313-1316.
• 42 Lutgens E, Cleutjens KB, Heeneman S. et al. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci USA 2000; 97: 7464-7469.
• 43 Mach F, Schönbeck U, Sukhova GK. et al. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998; 394: 200-203.
• 44 Schönbeck U, Sukhova GK, Shimizu K. et al. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci USA 2000; 97: 7458-7463.
• 45 Willecke F, Tiwari S, Rupprecht B. et al. Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice. Thromb Haemost 2014; 112: 379-389.
• 46 Donners MMPC, Beckers L, Lievens D. et al. The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling. Blood 2008; 111: 4596-4604.
• 47 Smook MLF, Heeringa P, Damoiseaux JGMC. et al. Leukocyte CD40L deficiency affects the CD25(+) CD4 T cell population but does not affect atherosclerosis. Atherosclerosis 2005; 183: 275-282.
• 48 Bavendiek U, Zirlik A, LaClair S. et al. Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells. Arterioscler Thromb Vasc Biol 2005; 25: 1244-1249.
• 49 Lievens D, Zernecke A, Seijkens T. et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116: 4317-4327.
• 50 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.
• 51 Zirlik A, Maier C, Gerdes N. et al. CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1. Circulation 2007; 115: 1571-1580.
• 52 Wolf D, Hohmann J-D, Wiedemann A. et al. Binding of CD40L to Mac-1’s I-domain involves the EQLKKSKTL motif and mediates leukocyte recruitment and atherosclerosis--but does not affect immunity and thrombosis in mice. Circ Res 2011; 109: 1269-1279.
• 53 Rub A, Dey R, Jadhav M. et al. Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function. Nat Immunol 2009; 10: 273-280.
• 54 Zirlik A, Bavendiek U, Libby P. et al. TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells. Arterioscler Thromb Vasc Biol 2007; 27: 1101-1107.
• 55 Missiou A, Köstlin N, Varo N. et al. Tumor necrosis factor receptor-associated factor 1 deficiency attenuates atherosclerosis in mice by impairing monocyte recruitment to the vessel wall. Circulation 2010; 121: 2033-2044.
• 56 Missiou A, Rudolf P, Stachon P. et al. TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory cell recruitment and foam cell formation. Circ Res 2010; 107: 757-766.
• 57 Stachon P, Missiou A, Walter C. et al. Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans. PLoS ONE 2010; 05: e11589.
• 58 Polykratis A, van Loo G, Xanthoulea S. et al. Conditional targeting of tumor necrosis factor receptor-associated factor 6 reveals opposing functions of Toll-like receptor signaling in endothelial and myeloid cells in a mouse model of atherosclerosis. Circulation 2012; 126: 1739-1751.
• 59 Song Z, Jin R, Yu S. et al. CD40 is essential in the upregulation of TRAF proteins and NF-kappaBdependent proinflammatory gene expression after arterial injury. PLoS ONE 2011; 06: e23239.
• 60 Song Z, Jin R, Yu S. et al. Crucial role of CD40 signaling in vascular wall cells in neointimal formation and vascular remodeling after vascular interventions. Arterioscler Thromb Vasc Biol 2012; 32: 50-64.
• 61 Poggi M, Jager J, Paulmyer-Lacroix O. et al. The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 2009; 52: 1152-1163.
• 62 Missiou A, Wolf D, Platzer I. et al. CD40L induces inflammation and adipogenesis in adipose cells--a potential link between metabolic and cardiovascular disease. Thromb Haemost 2010; 103: 788-796.
• 63 Seijkens T, Kusters P, Engel D. et al. CD40-CD40L: linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications. Diab Vasc Dis Res 2013; 10: 115-122.
• 64 Poggi M, Engel D, Christ A. et al. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice. Arterioscler Thromb Vasc Biol 2011; 31: 2251-2260.
• 65 Klein D, Timoneri F, Ichii H. et al. CD40 activation in human pancreatic islets and ductal cells. Diabetologia 2008; 51: 1853-1861.
• 66 Li H, Lelliott C, Håkansson P. et al. Intestinal, adipose, and liver inflammation in diet-induced obese mice. Metab Clin Exp 2008; 57: 1704-1710.
• 67 Baena-Fustegueras JA, Pardina E, Balada E. et al. Soluble CD40 ligand in morbidly obese patients: effect of body mass index on recovery to normal levels after gastric bypass surgery. JAMA Surg 2013; 148: 151-156.
• 68 Wolf D, Jehle F, Ortiz ARodriguez. et al. CD40L deficiency attenuates diet-induced adipose tissue inflammation by impairing immune cell accumulation and production of pathogenic IgG-antibodies. PLoS ONE 2012; 07: e33026.
• 69 Chatzigeorgiou A, Seijkens T, Zarzycka B. et al. Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci USA 2014; 111: 2686-2691.
• 70 Wolf D, Jehle F, Anto NMichel. et al. Co-Inhibitory Suppression of T Cell Activation by CD40 Protects from Obesity and Adipose Tissue Inflammation in Mice. Circulation 2014; 129: 2414-2525.
• 71 Guo C-A, Kogan S, Amano SU. et al. CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance. Am J Physiol Endocrinol Metab 2013; 304: E951-E963.
• 72 Yi Z, Stunz LL, Bishop GA. CD40-mediated maintenance of immune homeostasis in the adipose tissue microenvironment. Diabetes 2014; 63: 2751-2760.
• 73 Van den Berg SM, Seijkens TTP, Kusters PJH. et al. Blocking CD40-Traf6 interactions by small molecule inhibitor 6860766 ameliorates the complications of diet induced obesity in mice. Int J Obes (Lond) 2015; 39: 782-790.
• 74 Moreland L, Bate G, Kirkpatrick P. Abatacept. Nat Rev Drug Discov 2006; 05: 185-186.
• 75 Genovese MC, Becker J-C, Schiff M. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005; 353: 1114-1123.
• 76 Liossis S-NC, Sfikakis PP. Costimulation blockade in the treatment of rheumatic diseases. BioDrugs 2004; 18: 95-102.
• 77 Kanmaz T, Fechner JJH, Torrealba J. et al. Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model. Transplantation 2004; 77: 914-920.
• 78 Kasran A, Boon L, Wortel CH. et al. Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe Crohn’s disease. Aliment Pharmacol Ther 2005; 22: 111-122.
• 79 Beatty GL, Torigian DA, Chiorean EG. et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 2013; 19: 6286-6295.
• 80 De Vos S, Forero-Torres A, Ansell SM. et al. A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors. J Hematol Oncol 2014; 07: 44.