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 (FADDODC-KO). FADD mediates apoptosis by coupling death receptors with downstream caspase activation. In line with this, ODCs from FADDODC-KO mice were completely resistant to death receptor-induced apoptosis in vitro. In the EAE model, FADDODC-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.

[1]  Vishva Dixit,et al.  Death receptor signal transducers: nodes of coordination in immune signaling networks , 2009, Nature Immunology.

[2]  B. Trapp,et al.  Multiple sclerosis: an immune or neurodegenerative disorder? , 2008, Annual review of neuroscience.

[3]  A. Baxter,et al.  The origin and application of experimental autoimmune encephalomyelitis , 2007, Nature Reviews Immunology.

[4]  Amaia M. Arranz,et al.  P2X7 Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis , 2007, The Journal of Neuroscience.

[5]  A. Mildner,et al.  Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice , 2006, Nature Immunology.

[6]  B. Becher,et al.  Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. , 2006, The Journal of clinical investigation.

[7]  G. Kollias,et al.  Apoptosis of Oligodendrocytes via Fas and TNF-R1 Is a Key Event in the Induction of Experimental Autoimmune Encephalomyelitis1 , 2005, The Journal of Immunology.

[8]  M. Peter,et al.  Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities. , 2005, Molecular cell.

[9]  C. Matute,et al.  Multiple sclerosis: novel perspectives on newly forming lesions , 2005, Trends in Neurosciences.

[10]  S. Miller,et al.  Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis , 2005, Nature Medicine.

[11]  B. Becher,et al.  Experimental autoimmune encephalomyelitis repressed by microglial paralysis , 2005, Nature Medicine.

[12]  J. Russell,et al.  TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation , 2004, Journal of Neuroimmunology.

[13]  L. Cartier,et al.  Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells1 , 2004, The Journal of Immunology.

[14]  C. Matute,et al.  Caspase-Dependent and Caspase-Independent Oligodendrocyte Death Mediated by AMPA and Kainate Receptors , 2003, The Journal of Neuroscience.

[15]  H. Okano,et al.  Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination , 2003, Neuroscience Research.

[16]  A. Winoto,et al.  A function of Fas-associated death domain protein in cell cycle progression localized to a single amino acid at its C-terminal region. , 2003, Immunity.

[17]  S. Cook,et al.  Apoptotic death following Fas activation in human oligodendrocyte hybrid cultures , 2002, Journal of neuroscience research.

[18]  S. Miller,et al.  Epitope spreading in immune-mediated diseases: implications for immunotherapy , 2002, Nature Reviews Immunology.

[19]  George Kollias,et al.  Uncoupling the Proinflammatory from the Immunosuppressive Properties of Tumor Necrosis Factor (Tnf) at the P55 TNF Receptor Level , 2001, The Journal of experimental medicine.

[20]  H. Okano,et al.  Caspase-11 Mediates Oligodendrocyte Cell Death and Pathogenesis of Autoimmune-Mediated Demyelination , 2001, The Journal of experimental medicine.

[21]  K. Frei,et al.  TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease. , 2000, Brain : a journal of neurology.

[22]  Reynaldo Sequerra,et al.  High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP , 2000, Nature Genetics.

[23]  J. Miyazaki,et al.  Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune‐mediated demyelination , 2000, The EMBO journal.

[24]  J. Bluestone,et al.  Pathologic Role and Temporal Appearance of Newly Emerging Autoepitopes in Relapsing Experimental Autoimmune Encephalomyelitis1 , 2000, The Journal of Immunology.

[25]  M. Chao,et al.  Oligodendrocyte Apoptosis Mediated by Caspase Activation , 1999, The Journal of Neuroscience.

[26]  V. Tuohy,et al.  Spontaneous Regression of Primary Autoreactivity during Chronic Progression of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis , 1999, The Journal of experimental medicine.

[27]  A. MacKenzie-Graham,et al.  Temporal kinetics and cellular phenotype of TNF p55/p75 receptors in experimental allergic encephalomyelitis , 1999, Journal of Neuroimmunology.

[28]  R. Kinkel,et al.  The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis , 1998, Immunological reviews.

[29]  G. Evan,et al.  p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice , 1998, Current Biology.

[30]  A. Chinnaiyan,et al.  A role for FADD in T cell activation and development. , 1998, Immunity.

[31]  D. Goeddel,et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. , 1998, Science.

[32]  N. Kabra,et al.  Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1 , 1998, Nature.

[33]  Kenneth G. C. Smith,et al.  A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes , 1998, The EMBO journal.

[34]  S. Miller,et al.  Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading , 1997, Nature Medicine.

[35]  G. Chaudhri,et al.  Tumor necrosis factor blockade in actively induced experimental autoimmune encephalomyelitis prevents clinical disease despite activated T cell infiltration to the central nervous system , 1997, European journal of immunology.

[36]  J. Menonna,et al.  Cell death and birth in multiple sclerosis brain , 1997, Journal of the Neurological Sciences.

[37]  H. Okano,et al.  ICE/CED‐3 Family Executes Oligodendrocyte Apoptosis by Tumor Necrosis Factor , 1997, Journal of neurochemistry.

[38]  A. MacKenzie-Graham,et al.  Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia , 1997, Journal of Neuroimmunology.

[39]  J. Antel,et al.  Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death , 1996, The Journal of experimental medicine.

[40]  R. Dobrowsky,et al.  Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75 , 1996, Nature.

[41]  David Wallach,et al.  Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor–Induced Cell Death , 1996, Cell.

[42]  Matthias Mann,et al.  FLICE, A Novel FADD-Homologous ICE/CED-3–like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex , 1996, Cell.

[43]  Arul M. Chinnaiyan,et al.  FADD, a novel death domain-containing protein, interacts with the death domain of fas and initiates apoptosis , 1995, Cell.

[44]  J. Camonis,et al.  A Novel Protein That Interacts with the Death Domain of Fas/APO1 Contains a Sequence Motif Related to the Death Domain (*) , 1995, The Journal of Biological Chemistry.

[45]  K. Rajewsky,et al.  A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. , 1995, Nucleic acids research.

[46]  K. Jellinger,et al.  Patterns of oligodendroglia pathology in multiple sclerosis. , 1994, Brain : a journal of neurology.

[47]  C. Stewart,et al.  Simple screening procedure to detect gene targeting events in embryonic stem cells. , 1993, Methods in enzymology.

[48]  C. Buttinelli,et al.  Multiple sclerosis patients express increased levels of β-nerve growth factor in cerebrospinal fluid , 1992, Neuroscience Letters.

[49]  E. Sercarz,et al.  Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen , 1992, Nature.

[50]  M. Sharief,et al.  Association between Tumor Necrosis Factor-α and Disease Progression in Patients with Multiple Sclerosis , 1991 .

[51]  C. Brosnan,et al.  Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. , 1991, The Journal of clinical investigation.