Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

<jats:title>Abstract</jats:title><jats:p>The costimulatory CD40L–CD40 dyad plays a major role in multiple sclerosis (MS). CD40 is highly expressed on MHCII<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> cells in experimental autoimmune encephalomyelitis (EAE). Both <jats:italic>MHCII–CD40–Traf2</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> and <jats:italic>MHCII–CD40–Traf6</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice showed a reduction in clinical signs of EAE and prevented demyelination. However, only <jats:italic>MHCII–CD40–Traf6</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> 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 <jats:italic>CD40</jats:italic><jats:sup><jats:italic>flfl</jats:italic></jats:sup><jats:italic>LysM</jats:italic><jats:sup><jats:italic>cre</jats:italic></jats:sup> mice to EAE. This myeloid‐specific deletion of CD40 resulted in a significant reduction in EAE severity, reduced CNS inflammation and demyelination.</jats:p><jats:p>In conclusion, the CD40–TRAF6 signaling pathway in MHCII<jats:sup>+</jats:sup> 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. <jats:italic>The Journal of Pathology</jats:italic> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</jats:p>