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- Title
Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation.
- Authors
Aarts, Suzanne A. B. M.; Seijkens, Tom T. P.; Kusters, Pascal J. H.; van der Pol, Susanne M. A.; Zarzycka, Barbara; Heijnen, Priscilla D. A. M.; Beckers, Linda; den Toom, Myrthe; Gijbels, Marion J. J.; Boon, Louis; Weber, Christian; de Vries, Helga E.; Nicolaes, Gerry A. F.; Dijkstra, Christine D.; Kooij, Gijs; Lutgens, Esther
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
MULTIPLE sclerosis diagnosis; MULTIPLE sclerosis treatment; CENTRAL nervous system; LEUCOCYTES; BLOOD-brain barrier; TUMOR necrosis factors
- Publication
Journal of Neuroinflammation, 2017, Vol 14, p1
- ISSN
1742-2094
- Publication type
journal article
- DOI
10.1186/s12974-017-0875-9