CD40-TRAF6, mTOR and S6K1 targeted inhibition of macrophage dynamics resolves atherosclerotic plaque inflammation

In atherosclerosis, macrophage accumulation is directly linked to destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T-lymphocytes through CD40-CD40 ligand signaling. Here we show that interruption of this signaling pathway in monocyte / macrophage exerts rapid anti-inflammatory effects in an Apoe-/- mouse model of atherosclerosis. For this purpose we developed an infusible recombinant high-density lipoprotein nanoparticle carrying small molecule inhibitor of the interaction of CD40s and tumor necrosis factor receptor-associated factor 6. We show monocyte / macrophage specific targeting of our nanoimmunotherapy, which impairs their migratory capacity. Rapid induction of plaque inflammation by this therapy represents a novel strategy in the treatment of atherosclerosis, with high potential for clinical translation, as illustrated by the favorable toxicity profile in non-human primates. 39 atherosclerosis samples sequenced, 10 treated with TRAF6i-HDL, 10 treated with PBS as control, 10 treated with mTORi-HDL and another 9 treated with S6K1i-HDL.