Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination.
Apoptosis of oligodendrocytes (ODCs), the myelin-producing glial cells in the CNS, plays a central role in demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To investigate the mechanism behind ODC apoptosis in EAE, we made use of conditional knockout mice lacking the adaptor protein FADD specifically in ODCs (FADD(ODC-KO)). FADD mediates apoptosis by coupling death receptors with downstream caspase activation. In line with this, ODCs from FADD(ODC-KO) mice were completely resistant to death receptor-induced apoptosis in vitro. In the EAE model, FADD(ODC-KO) mice followed an ameliorated clinical disease course in comparison with control littermates. Lymphocyte and macrophage infiltration into the spinal cord parenchyma was significantly reduced, as was the extent of demyelination and proinflammatory gene expression. Collectively, our data show that FADD is critical for ODC apoptosis and the development of autoimmune demyelinating disease.
Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
Conor
C
Mc Guire
Thomas
T
Volckaert
Uta
U
Wolke
Mozes
M
Sze
Riet
R
de Rycke
Ari
A
Waisman
Marco
M
Prinz
Rudi
R
Beyaert
Manolis
M
Pasparakis
Geert
G
van Loo
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein