Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

Aarts, Suzanne A. B. M.; Seijkens, Tom T. P.; Kusters, Pascal J. H.; van Tiel, Claudia M.; Reiche, Myrthe E.; den Toom, Myrthe; Beckers, Linda; van Roomen, Cindy P. A. A.; de Winther, Menno P. J.; Kooij, Gijs and Lutgens, Esther (2019): Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis. In: Journal of Pathology, Vol. 247, No. 4: pp. 471-480

Abstract

The costimulatory 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 TNF receptor-associated factor 2 (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 CNS that was accompanied by reduced levels of TNF-alpha, IL-6 and IFN-gamma. As CD40-TRAF6 interactions predominantly occur in macrophages, we subjected CD40(flfl)LysM(cre) 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 neuroinflammation and demyelination during EAE. Concomitant with the fact that CD40-TRAF6 interactions are predominant in macrophages, depletion of myeloid CD40 also reduces neuroinflammation. CD40-TRAF6 interactions thus represent a promising therapeutic target for MS. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0022-3417
• Language: English