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Answering this question is of special interest in globoid cell leukodystrophy (GLD), a genetic fatal demyelinating disease, because its rapidly progressive demyelination in the nervous system is accompanied by a characteristic accumulation of numerous globoid macrophages. Therefore, we cross-bred the twitcher (<jats:italic>twi<\/jats:italic>) mouse, a bona fide model of GLD, with the macrophage-deficient osteopetrotic mutant and studied the resultant macrophage-deficient twitcher (<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>) mouse. The<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>mouse had few microglia and macrophages in the white matter and, interestingly, showed a more severe clinical phenotype compared to the<jats:italic>twi<\/jats:italic>mouse. The number of nonmyelinated axons in the spinal cord was significantly higher in<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>mice than in<jats:italic>twi<\/jats:italic>mice at 45 d old. The difference appeared to be due to impaired remyelination in<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>mice rather than accelerated demyelination. Quantitative reverse transcription PCR and immunohistochemical studies revealed that the recruitment of oligodendrocyte progenitor cells in response to demyelination was compromised in<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>mice. Increased myelin debris in the white matter parenchyma of<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>mice suggested that phagocytosis by macrophages may play an important role in promoting remyelination. Macrophage markers for both protective and destructive phenotypes were significantly upregulated in the spinal cord of<jats:italic>twi<\/jats:italic>mice but were close to normal in<jats:italic>twi<\/jats:italic>+<jats:italic>op<\/jats:italic>mice due to the reduced macrophage number. The overall effects of macrophages in GLD appear to be beneficial to myelin by promoting myelin repair.<\/jats:p>","DOI":"10.1523\/jneurosci.6344-10.2011","type":"journal-article","created":{"date-parts":[[2011,3,9]],"date-time":"2011-03-09T18:40:31Z","timestamp":1299696031000},"page":"3610-3624","source":"Crossref","is-referenced-by-count":56,"title":["Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy"],"prefix":"10.1523","volume":"31","author":[{"given":"Yoichi","family":"Kondo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie T.","family":"Vanier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2011,3,9]]},"reference":[{"key":"2023041303492258000_31.10.3610.1","doi-asserted-by":"publisher","DOI":"10.1038\/nn738"},{"key":"2023041303492258000_31.10.3610.2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.1.427"},{"key":"2023041303492258000_31.10.3610.3","doi-asserted-by":"crossref","first-page":"9824","DOI":"10.1523\/JNEUROSCI.23-30-09824.2003","article-title":"Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration","volume":"23","author":"Arnett","year":"2003","journal-title":"J Neurosci"},{"key":"2023041303492258000_31.10.3610.4","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1097\/00005072-196504000-00008","article-title":"Studies in globoid (Krabbe) leukodystrophy. 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