J Pathol. 2018 Nov 24. doi: 10.1002/path.5205. [Epub ahead of print]
Aarts, SABM; Seijkens, TTP; Kusters, PJH; van Tiel, CM; Reiche, ME; den Toom, M; Beckers, L; van Roomen, CPAA; de Winther, MPJ; Kooji, G; Lutgens, E
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Amsterdam University Medical Centers, location AMC, Amsterdam Cardiovascular Sciences (ACS), University of Amsterdam, 1105, AZ, Amsterdam, The Netherlands. Institute for C
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.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 400 scientific publications are based on research using Ozgene mice.