Central Illustration.

TRAF-STOP Treatment Reduces Atherosclerosis and Preserves Immunity

Binding of CD40L to CD40 results in the recruitment of tumor necrosis factor receptor-associated factors (TRAFs), and propagation of signaling. The C-terminal part of CD40 contains a TRAF2/3/5 binding domain and a TRAF6 binding domain that both induce nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription. CD40-TRAF6 interactions are the predominant signal transduction route in macrophages, and are important in atherosclerosis, whereas CD40-TRAF2/3/5 interactions are important in CD40 driven immunity in other cell types, including dendritic cells (DCs) and B cells. Small molecule inhibitors of the CD40-TRAF6 interactions (TRAF-STOPs) inhibit CD40-induced activation of the canonical NF-κB pathway and subsequent cytokine and chemokine production. TRAF-STOPs are particularly effective in monocytes/macrophages and hamper monocyte recruitment, macrophage activation, and foam cell formation. Consequently, both de novo and established atherosclerosis are reduced upon TRAF-STOP treatment. By keeping CD40-TRAF2/3/5 interactions intact, CD40-mediated immunity is preserved, and immune suppressive side effects are prevented. MHC = major histocompatibility complex; TCR = T cell receptor.