Macrophage CD40-signaling drives experimental autoimmune encephalomyelitis

Suzanne A B M Aarts, Tom T P Seijkens, Pascal J H Kusters, Claudia M van Tiel, Myrthe E Reiche, Myrthe den Toom, Linda Beckers, Cindy P A A van Roomen, Menno P J de Winther, Gijs Kooij, Esther Lutgens

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The co-stimulatory CD40L-CD40 dyad plays a major role in multiple sclerosis (MS). CD40 is highly expressed on MHCII+ B cells, dendritic cells and macrophages in human MS lesions. Here we investigated the role of the CD40 downstream signaling intermediates TRAF2 and TRAF6 in MHCII+ cells in experimental autoimmune encephalomyelitis (EAE). Both MHCII-CD40-Traf2-/- and MHCII-CD40-Traf6-/- mice showed a reduction in clinical signs of EAE and prevented demyelination. However, only MHCII-CD40-Traf6-/- mice displayed a decrease in myeloid and lymphoid cell infiltration into the central nervous system (CNS) that was accompanied by reduced levels of TNF-α, IL-6, and IFN-γ. As CD40-TRAF6 interactions predominantly occur in macrophages, we subjected CD40flfl LysMcre mice to EAE. This myeloid specific deletion of CD40 resulted in a significant reduction in EAE severity, reduced CNS inflammation and demyelination. In conclusion, the CD40-TRAF6 signaling pathway in MHCII+ cells plays a key role in neuro-inflammation and demyelination during EAE. Concomitant with the fact that CD40-TRAF6 interactions are predominant in macrophages, depletion of myeloid CD40 also reduces neuro-inflammation. CD40-TRAF6 interactions thus represent a promising therapeutic target for multiple sclerosis.

Original languageEnglish
Pages (from-to)471-480
Number of pages10
JournalJournal of Pathology
Volume247
Issue number4
Early online date24 Nov 2018
DOIs
Publication statusPublished - 1 Apr 2019

Cite this

Aarts, S. A. B. M., Seijkens, T. T. P., Kusters, P. J. H., van Tiel, C. M., Reiche, M. E., den Toom, M., ... Lutgens, E. (2019). Macrophage CD40-signaling drives experimental autoimmune encephalomyelitis. Journal of Pathology, 247(4), 471-480. https://doi.org/10.1002/path.5205