TRAF-STOPping atherosclerosis: targeting of CD40-induced TRAF6 signaling in macrophages reduces (established) atherosclerosis

Inhibition of the costimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage can result in immune suppression. We recently identified small molecule inhibitors that block the interaction between CD40 and TNF Receptor Associated Factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. Here we further characterized the working mechanisms of TRAF-STOPs 6877002 and 6860766 in atherogenesis. Transcriptional profiling in CD40-activated macrophages showed that TRAF-STOP 6877002 had profound effects on the clusters ‘immune responses’ and ‘cell cycle progression’, whereas TRAF-STOP 6860766 only affected ‘immune responses’. Comparison of gene expression in bone marrow-derived macrophages of C57Bl6 mice (n=3) pre-incubated with vehicle (CTRL) or compound TRAF-STOP 6877002 or TRAF-STOP 6860766 (3 mice/group) for 1 hour and subsequently activated by the agonistic CD40 antibody FGK45.