Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

• Published in: The Journal of pathology Vol. 247; no. 4; pp. 471 - 480
• Main Authors: Aarts, Suzanne ABM, Seijkens, Tom TP, Kusters, Pascal JH, van Tiel, Claudia M, Reiche, Myrthe E, den Toom, Myrthe, Beckers, Linda, van Roomen, Cindy PAA, de Winther, Menno PJ, Kooij, Gijs, Lutgens, Esther
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-04-2019; Wiley Subscription Services, Inc
• Subjects: Animals; Autoantibodies - metabolism; CD40; CD40 antigen; CD40 Antigens - deficiency; CD40 Antigens - physiology; CD40 Ligand - physiology; CD40L protein; Clonal deletion; Cytokines - metabolism; Demyelination; Dendritic cells; Depletion; Encephalomyelitis, Autoimmune, Experimental - immunology; Experimental allergic encephalomyelitis; experimental autoimmune encephalomyelitis; Female; Immunoglobulin G - immunology; Inflammation; Interferon; Intermediates; Lesions; Lymphocytes B; Macrophages; Macrophages - immunology; Mice; Mice, Inbred C57BL; Multiple sclerosis; Multiple Sclerosis - immunology; Myelin-Oligodendrocyte Glycoprotein - immunology; Neuritis - immunology; Original Paper; Original Papers; Signal transduction; Signal Transduction - immunology; Therapeutic applications; TNF Receptor-Associated Factor 6 - physiology; TNF receptor‐associated peptides and proteins; TRAF2 protein; TRAF6 protein; Tumor necrosis factor; Tumor necrosis factor receptors; CD40; macrophages; experimental autoimmune encephalomyelitis; multiple sclerosis; TNF receptor-associated peptides and proteins
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.5205

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‐α, IL‐6 and IFN‐γ. As CD40–TRAF6 interactions predominantly occur in macrophages, we subjected CD40flflLysMcre 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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.