Mus musculus Transcriptome or Gene expression

In atherosclerosis, macrophage accumulation is directly linked to destabilization and rupture of plaques, 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 monocytes/macrophages exerts rapid anti-inflammatory effects in an Apoe-/- mouse model of atherosclerosis. For this purpose, we developed an infusible reconstituted high-density lipoprotein nanoparticle carrying a small molecule inhibitor of the interaction of CD40 and tumor necrosis factor receptor-associated factor 6. We show monocyte/macrophage specific targeting of our nano-immunotherapy, which impairs their migratory capacity. Rapid reduction 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.