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Seijkens, Tom T. P.; Tiel, Claudia M. van; Kusters, Pascal J. H.; Atzler, Dorothee; Soehnlein, Oliver; Zarzycka, Barbara; Aarts, Suzanne A. B. M.; Lameijer, Marnix; Gijbels, Marion J.; Beckers, Linda; Toom, Myrthe den; Slutter, Bram; Kuiper, Johan; Duchene, Johan; Aslani, Maria; Megens, Remco T. A.; Veer, Cornelis van 't; Kooij, Gijs; Schrijver, Roy; Hoeksema, Marten A.; Boon, Louis; Fay, Francois; Tang, Jun; Baxter, Samantha; Jongejan, Aldo; Moerland, Perry D.; Vriend, Gert; Bleijlevens, Boris; Fisher, Edward A.; Duivenvoorden, Raphael; Gerdes, Norbert; Winther, Menno P. J. de; Nicolaes, Gerry A.; Mulder, Willem J. M.; Weber, Christian; Lutgens, Esther (2018): Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. In: Journal of the American College of Cardiology, Vol. 71, No. 5: pp. 527-542
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Abstract

BACKGROUND Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. OBJECTIVES This study evaluates the potential of TRAF-STOP treatment in atherosclerosis. METHODS The effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe(-/-)) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages. RESULTS TRAF-STOP treatment of young Apoe(-/-) mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe(-/-) mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair " classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and beta 2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-kappa B pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe(-/-) mice. CONCLUSIONS TRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis. Published by Elsevier on behalf of the American College of Cardiology Foundation.