PMID- 30471110
OWN - NLM
STAT- MEDLINE
DCOM- 20191216
LR  - 20200309
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Print)
IS  - 0022-3417 (Linking)
VI  - 247
IP  - 4
DP  - 2019 Apr
TI  - Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis.
PG  - 471-480
LID - 10.1002/path.5205 [doi]
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-alpha, IL-6 
      and IFN-gamma. 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. (c) 2018 The 
      Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of 
      Pathological Society of Great Britain and Ireland.
CI  - (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd 
      on behalf of Pathological Society of Great Britain and Ireland.
FAU - Aarts, Suzanne Abm
AU  - Aarts SA
AUID- ORCID: 0000-0003-4608-3705
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - Seijkens, Tom Tp
AU  - Seijkens TT
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
AD  - Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University 
      (LMU), Munich, Germany.
FAU - Kusters, Pascal Jh
AU  - Kusters PJ
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - van Tiel, Claudia M
AU  - van Tiel CM
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - Reiche, Myrthe E
AU  - Reiche ME
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - den Toom, Myrthe
AU  - den Toom M
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - Beckers, Linda
AU  - Beckers L
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - van Roomen, Cindy Paa
AU  - van Roomen CP
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
FAU - de Winther, Menno Pj
AU  - de Winther MP
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
AD  - Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University 
      (LMU), Munich, Germany.
AD  - Department of Molecular Cell Biology and Immunology, Amsterdam University Medical 
      Centers, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
FAU - Kooij, Gijs
AU  - Kooij G
AD  - Department of Molecular Cell Biology and Immunology, Amsterdam University Medical 
      Centers, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
FAU - Lutgens, Esther
AU  - Lutgens E
AUID- ORCID: 0000-0002-2609-5744
AD  - Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, 
      Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences (ACS), 
      University of Amsterdam, Arizona, Amsterdam, The Netherlands.
AD  - Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University 
      (LMU), Munich, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190130
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Autoantibodies)
RN  - 0 (CD40 Antigens)
RN  - 0 (Cytokines)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Myelin-Oligodendrocyte Glycoprotein)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 147205-72-9 (CD40 Ligand)
SB  - IM
MH  - Animals
MH  - Autoantibodies/metabolism
MH  - CD40 Antigens/deficiency/*physiology
MH  - CD40 Ligand/physiology
MH  - Cytokines/metabolism
MH  - Encephalomyelitis, Autoimmune, Experimental/*immunology
MH  - Female
MH  - Immunoglobulin G/immunology
MH  - Macrophages/*immunology
MH  - Mice, Inbred C57BL
MH  - Multiple Sclerosis/immunology
MH  - Myelin-Oligodendrocyte Glycoprotein/immunology
MH  - Neuritis/immunology
MH  - Signal Transduction/*immunology
MH  - TNF Receptor-Associated Factor 6/*physiology
PMC - PMC6519352
OTO - NOTNLM
OT  - CD40
OT  - TNF receptor-associated peptides and proteins
OT  - experimental autoimmune encephalomyelitis
OT  - macrophages
OT  - multiple sclerosis
EDAT- 2018/11/25 06:00
MHDA- 2019/12/18 06:00
PMCR- 2019/05/15
CRDT- 2018/11/25 06:00
PHST- 2018/07/16 00:00 [received]
PHST- 2018/10/23 00:00 [revised]
PHST- 2018/11/19 00:00 [accepted]
PHST- 2018/11/25 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2018/11/25 06:00 [entrez]
PHST- 2019/05/15 00:00 [pmc-release]
AID - PATH5205 [pii]
AID - 10.1002/path.5205 [doi]
PST - ppublish
SO  - J Pathol. 2019 Apr;247(4):471-480. doi: 10.1002/path.5205. Epub 2019 Jan 30.