Abstract
Multiple sclerosis is an autoimmune disease in which self-reactive T cells attack oligodendrocytes that myelinate axons in the CNS. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is dependent on caspase-1; however, the role of Nod-like receptors upstream of caspase-1 is unknown. Danger- and pathogen-associated molecular patterns activate Nod-like receptor 3, which activates caspase-1 through the adaptor protein, apoptosis-associated speck-like protein containing CARD (ASC). We report that the progression of EAE is dependent on ASC and caspase-1 but not Nod-like receptor 3. ASC(-/-) mice were even more protected from the progression of EAE than were caspase-1(-/-) mice, suggesting that an inflammasome-independent function of ASC contributes to the progression of EAE. We found that CD4(+) T cells deficient in ASC exhibited impaired survival; accordingly, ASC(-/-) mice had fewer myelin oligodendrocyte glycoprotein-specific T cells in the draining lymph nodes and CNS.
Publication types
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Research Support, N.I.H., Extramural
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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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CARD Signaling Adaptor Proteins / deficiency
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / physiology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Carrier Proteins / physiology
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Caspase 1 / physiology
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Cell Proliferation
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Cell Survival / genetics
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Cell Survival / immunology
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Cells, Cultured
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Central Nervous System / immunology
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Central Nervous System / pathology
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Cytokines / biosynthesis
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Disease Progression
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Encephalomyelitis, Autoimmune, Experimental / enzymology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymphopenia / genetics
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Lymphopenia / immunology
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Lymphopenia / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myelin Proteins
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Myelin-Associated Glycoprotein / toxicity
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Myelin-Oligodendrocyte Glycoprotein
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NLR Family, Pyrin Domain-Containing 3 Protein
Substances
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytokines
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Mog protein, mouse
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Caspase 1