TY - JOUR
T1 - Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis
AU - Aarts, Suzanne A.B.M.
AU - Seijkens, Tom T.P.
AU - Kusters, Pascal J.H.
AU - van Tiel, Claudia M.
AU - Reiche, Myrthe E.
AU - den Toom, Myrthe
AU - Beckers, Linda
AU - van Roomen, Cindy P.A.A.
AU - de Winther, Menno P.J.
AU - Kooij, Gijs
AU - Lutgens, Esther
N1 - Publisher Copyright:
© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
PY - 2019/4
Y1 - 2019/4
N2 - 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 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.
AB - 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 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.
KW - CD40
KW - TNF receptor-associated peptides and proteins
KW - experimental autoimmune encephalomyelitis
KW - macrophages
KW - multiple sclerosis
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U2 - 10.1002/path.5205
DO - 10.1002/path.5205
M3 - Article
C2 - 30471110
AN - SCOPUS:85060974109
SN - 0022-3417
VL - 247
SP - 471
EP - 480
JO - Journal of Pathology
JF - Journal of Pathology
IS - 4
ER -