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The Journal of Neuroscience, October 29, 2003, 23(30):9824-9832
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Development/Plasticity/Repair
Functional Genomic Analysis of Remyelination Reveals Importance of Inflammation in Oligodendrocyte Regeneration
Heather A. Arnett,1,2 *
Ying Wang,1,3 *
Glenn K. Matsushima,2,3
Kinuko Suzuki,2,4 and
Jenny P.-Y. Ting1,2,3
1Lineberger Comprehensive Cancer Center, 2Neuroscience Center, and Departments of 3Microbiology–Immunology and 4Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599
Tumor necrosis factor  (TNF), a proinflammatory cytokine, was shown previously to promote remyelination and oligodendrocyte precursor proliferation in a murine model for demyelination and remyelination. We used Affymetrix microarrays in this study to identify (1) changes in gene expression that accompany demyelination versus remyelination and (2) changes in gene expression during the successful remyelination of wild-type mice versus the unsuccessful attempts in mice lacking TNF. Alterations in inflammatory genes represented the most prominent changes, with major histocompatibility complex (MHC) genes dramatically enhanced in microglia and astrocytes during demyelination, remyelination, and as a consequence of TNF stimulation. Studies to examine the roles of these genes in remyelination were then performed using mice lacking specific genes identified by the microarray. Analysis of MHC-II-null mice showed delayed remyelination and regeneration of oligodendrocytes, whereas removal of MHC-I had little effect. These data point to the induction of MHC-II by TNF as an important regulatory event in remyelination and emphasize the active inflammatory response in regeneration after pathology in the brain.
Key words: oligodendrocytes; glia; neuroinflammation; regeneration; major histocompatibility complex; gene array; multiple sclerosis; remyelination; demyelination; TNF
Received March 31, 2003;
revised July 25, 2003;
accepted July 29, 2003.
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