Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation

Background: the influx of leukocytes into the central nervous system (cns) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (ms). strategies that aim to inhibit leukocyte migration across the blood-brain barrier (bbb) are therefore regarded as promising therapeutic approaches to combat ms. as the cd40l-cd40 dyad signals via tnf receptor-associated factor 6 (traf6) in myeloid cells to induce inflammation and leukocyte trafficking,we explored the hypothesis that specific inhibition of cd40-traf6 interactions can ameliorate neuro-inflammation. methods: human monocytes were treated with a small molecule inhibitor (smi) of cd40-traf6 interactions (6877002),and migration capacity across human brain endothelial cells was measured. to test the therapeutic potential of the cd40-traf6-blocking smi under neuro-inflammatory conditions in vivo,lewis rats and c57bl/6j mice were subjected to acute experimental autoimmune encephalomyelitis (eae) and treated with smi 6877002 for 6 days (rats) or 3 weeks (mice). results: we here show that a smi of cd40-traf6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. moreover,upon smi treatment,monocytes displayed a decreased production of ros,tumor necrosis factor (tnf),and interleukin (il)-6,whereas the production of the anti-inflammatory cytokine il-10 was increased. disease severity of eae was reduced upon smi treatment in rats,but not in mice. however,a significant reduction in monocyte-derived macrophages,but not in t cells,that had infiltrated the cns was eminent in both models. conclusions: together,our results indicate that smi-mediated inhibition of the cd40-traf6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity,and is able to reduce cns-infiltrated monocyte-derived macrophages during neuro-inflammation,but minimally ameliorates eae disease severity. we therefore conclude that smi-mediated inhibition of the cd40-traf6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the cns and has the potential to be used as a co-treatment to combat ms. © 2017 the author(s).