Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Fas-Associated Death Domain Protein / biosynthesis
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Fas-Associated Death Domain Protein / genetics
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Fas-Associated Death Domain Protein / immunology*
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Gene Deletion*
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / pathology
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Lymphocytes / immunology
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Lymphocytes / metabolism
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Lymphocytes / pathology
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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Mice, Knockout
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Multiple Sclerosis / genetics
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Multiple Sclerosis / immunology*
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Multiple Sclerosis / metabolism
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Multiple Sclerosis / pathology
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Myelin Sheath / immunology
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Myelin Sheath / metabolism
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Myelin Sheath / pathology
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Oligodendroglia / immunology*
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Oligodendroglia / metabolism
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Oligodendroglia / pathology
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Spinal Cord / immunology
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Spinal Cord / metabolism
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Spinal Cord / pathology
Substances
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Fadd protein, mouse
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Fas-Associated Death Domain Protein