Function of co-stimulatory pathways in atheroslerosis
Final Report Abstract
The immune system plays a decisive role in the development and progression of atherosclerotic plaques. Key players in modulating immune responses are co-stimulatory and coinhibitory molecules that direct the phenotypes of T cells, dendritic cells (DC) and macrophages towards an effector (pro-inflammatory) or regulatory (anti-inflammatory) profile, and regulate the expression of adhesion molecules, cytokines, chemokines and their receptors. Co-stimulatory molecules act at the 'immunological synapse', i.e. where the T cell receptor interacts with major histocompatibility complex (MHC) on antigen-presenting cells (APCs), such as B cells, DCs, macrophages. Some co-stimulatory molecules can also generate more peripheral immunological responses on endothelial cells, smooth muscle cells, and platelets. In atherosclerosis, inhibition of the co-stimulatory CD40-CD154 (CD40 ligand)-dyad markedly reduces atherosclerosis. However, whether inhibition of CD154 or CD40 is athero-protective depends on the cell types and CD40-TRAF (Tumor Necrosis Factor Receptor Associated Factor) signaling pathways involved. In addition, inhibition of CD40-CD154 interactions not only changes the local immunological milieu of the plaque, but also affects the systemic immune system by converting T cells, DCs and macrophages into effector or regulatory immune cells. The CD40-CD154 system is a unique dyad, as it is not strictly a mediator of T cell activation, but mainly functions to activate APCs. Depending on the pathology, APCs express a plethora of co-stimulatory molecules, which in turn activate T cells and determine the phenotype of the T cell and the APC. This suggests that the reduction in atherosclerosis and the stable plaque phenotype due to inhibition of CD154/CD40 may be mediated via actions of other co-stimulatory dyads, function of which may be influences by CD40/CD154-dependent signaling. In the present project, we have shown the CD40-CD154 system can induce upregulation of other co-stimulatory receptor-ligand dyads like CTLA-4-B7.1/2, GITR-GITRL, and CD27-CD70. In this proposal we have investigated the role of CTLA-4, GITR, GITRL, CD27, and CD70 in atherosclerosis, as well as their effects on the immune system by using ‘gain and loss of function’ animal models. We have found that deficiency of GITR halts atherosclerosis, predominantly via inhibition of leukocyte recruitment via endothelial cell GITRL. On the other hand, overexpression of GITRL in the hematopoietic system protects against atherosclerosis via the induction of regulatory T-cells. Although CTLA4 is a strong co-inhibitory molecule, it has only minor effects on atherosclerosis development and progression. CD27 is another costimulatory molecule that is induced by CD40. Deficiency of total CD27, as well as deficiency of hematopoietic CD27 results in a strong increase in atherosclerosis. We found that this was due to a decrease in regulatory T-cells, which showed an increased apoptosis rate in the thymus. For CD70-/- mice, a similar phenotype was observed. Finally, we generated conditional CD40 and CD40L deficient mice, which we are currently backcrossing to ApoE-/- mice, and cell type specific Cre-transgenic mice. This will enable us to unravel the cell-type specific function of CD40L and CD40 in atherosclerosis. Collectively, this project has revealed the contribution of different CD40-induced co-stimulatory molecules in atherosclerosis. We have found that the co-stimulatory system is tightly regulated and that each co-stimulatory molecule exerts its own functions in atherosclerosis. These insights have helped us to understand the important, but versatile role of costimulation in atherogenesis. With this knowledge, we are one step further in the development of new therapeutic targets that bear the potential of inhibiting atherosclerosis via mediating (CD40-induced) co-stimulation.
Publications
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Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood. 2010;116:4317-27
Lievens D, Zernecke A, Seijkens T, Soehnlein O, Beckers L, Munnix IC, Wijnands E, Goossens P, van Kruchten R, Thevissen L, Boon L, Flavell RA, Noelle RJ, Gerdes N, Biessen EA, Daemen MJ, Heemskerk JW, Weber C, Lutgens E
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Abrogated transforming growth factor beta receptor II (TGFβRII) 51mmune51ng in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis. Eur Heart J. 2013;34:3717-27
Lievens D, Habets KL, Robertson AK, Laouar Y, Winkels H, Rademakers T, Beckers L, Wijnands E, Boon L, Mosaheb M, Ait-Oufella H, Mallat Z, Flavell RA, Rudling M, Binder CJ, Gerdes N, Biessen EA, Weber C, Daemen MJ, Kuiper J, Lutgens E
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Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol Med. 2013;5:471-81
Soehnlein O, Drechsler M, Döring Y, Lievens D, Hartwig H, Kemmerich K, Ortega-Gómez A, Mandl M, Vijayan S, Projahn D, Garlichs CD, Koenen RR, Hristov M, Lutgens E, Zernecke A, Weber C
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Inflammation and immune system interactions in atherosclerosis. Cell Mol Life Sci. 2013;70:3847-69
Legein B, Temmerman L, Biessen EA, Lutgens E
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Lymphocytic tumor necrosis factor receptor superfamily costimulatory molecules in the pathogenesis of atherosclerosis. Curr Opin Lipidol. 2013;24:518-24
Smeets E, Meiler S, Lutgens E
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Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res. 2014 23;114:1772-87
Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, Weih F, Weber C, Gerdes N, Habenicht AJ
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Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci USA. 2014;111:2686-91
Chatzigeorgiou A, Seijkens T, Zarzycka B, Engel D, Poggi M, van den Berg S, van den Berg S, Soehnlein O, Winkels H, Beckers L, Lievens D, Driessen A, Kusters P, Biessen E, Garcia-Martin R, Klotzsche-von Ameln A, Gijbels M, Noelle R, Boon L, Hackeng T, Schulte KM, Xu A, Vriend G, Nabuurs S, Chung KJ, Willems van Dijk K, Rensen PC, Gerdes N, de Winther M, Block NL, Schally AV, Weber C, Bornstein SR, Nicolaes G, Chavakis T, Lutgens E
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Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis. FASEB J. 2014;28:2202-13
Seijkens T, Hoeksema MA, Beckers L, Smeets E, Meiler S, Levels J, Tjwa M, de Winther MP, Lutgens E
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Mast cells control the expansion and differentiation of IL-10-competent B cells. J Immunol. 2014;193:4568-79
Mion F, D'Incà F, Danelli L, Toffoletto B, Guarnotta C, Frossi B, Burocchi A, Rigoni A, Gerdes N, Lutgens E, Tripodo C, Colombo MP, Rivera J, Vitale G, Pucillo CE
