Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)471-480
Number of pages10
JournalJournal of Pathology
Volume247
Issue number4
DOIs
StatePublished - Apr 2019

Keywords

  • CD40
  • experimental autoimmune encephalomyelitis
  • macrophages
  • multiple sclerosis
  • TNF receptor-associated peptides and proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint

Dive into the research topics of 'Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis'. Together they form a unique fingerprint.

Cite this