Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis.
Research paper by
Tom T P TTP Seijkens, Claudia M CM van Tiel, Pascal J H PJH Kusters, Dorothee D Atzler, Oliver O Soehnlein, Barbara B Zarzycka, Suzanne A B M SABM Aarts, Marnix M Lameijer, Marion J MJ Gijbels, Linda L Beckers, Myrthe M den Toom, Bram B Slütter, Johan J Kuiper, Johan J Duchene, Maria M Aslani, Remco T A RTA Megens, Cornelis C van 't Veer, Gijs G Kooij, Roy R Schrijver, Marten A MA Hoeksema, Louis L Boon, Francois F Fay, Jun J Tang, Samantha S Baxter, Aldo A Jongejan, Perry D PD Moerland, Gert G Vriend, Boris B Bleijlevens, Edward A EA Fisher, Raphael R Duivenvoorden, Norbert N Gerdes, Menno P J MPJ de Winther, Gerry A GA Nicolaes, Willem J M WJM Mulder, Christian C Weber, Esther E Lutgens
7th Feb 2018
7th Feb 2018
JACC (Journal of the American College of Cardiology)
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.This study evaluates the potential of TRAF-STOP treatment in atherosclerosis.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.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.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.