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 Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU), 80336, Munich, Germany. Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, location VUmc, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
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.