Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Tom T. P. Seijkens, Claudia M. van Tiel, Pascal J. H. Kusters, Dorothee Atzler, Oliver Soehnlein, Barbara Zarzycka, Suzanne A. B. M. Aarts, Marnix Lameijer, Marion J. Gijbels, Linda Beckers, Myrthe den Toom, Bram Slütter, Johan Kuiper, Johan Duchene, Maria Aslani, Remco T. A. Megens, Cornelis van ‘t Veer, Gijs Kooij, Roy Schrijver, Marten A. HoeksemaLouis Boon, Francois Fay, Jun Tang, Samantha Baxter, Aldo Jongejan, Perry D. Moerland, Gert Vriend, Boris Bleijlevens, Edward A. Fisher, Raphael Duivenvoorden, Norbert Gerdes, Menno P. J. de Winther, Gerry A. Nicolaes, Willem J. M. Mulder, Christian Weber, Esther Lutgens

Research output: Contribution to journalArticleAcademicpeer-review

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 β2-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-κB 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.
Original languageEnglish
Pages (from-to)527-542
Number of pages16
JournalJournal of the American College of Cardiology
Volume71
Issue number5
DOIs
Publication statusPublished - 2018

Cite this

Seijkens, T. T. P., van Tiel, C. M., Kusters, P. J. H., Atzler, D., Soehnlein, O., Zarzycka, B., ... Lutgens, E. (2018). Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. Journal of the American College of Cardiology, 71(5), 527-542. https://doi.org/10.1016/j.jacc.2017.11.055, https://doi.org/10.1016/j.jacc.2017.11.055