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Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the<jats:italic>tlr4<\/jats:italic>gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.<\/jats:p>","DOI":"10.1523\/jneurosci.22-07-02478.2002","type":"journal-article","created":{"date-parts":[[2018,4,13]],"date-time":"2018-04-13T22:30:10Z","timestamp":1523658610000},"page":"2478-2486","source":"Crossref","is-referenced-by-count":584,"title":["The Toll-Like Receptor TLR4 Is Necessary for Lipopolysaccharide-Induced Oligodendrocyte Injury in the CNS"],"prefix":"10.1523","volume":"22","author":[{"given":"Seija","family":"Lehnardt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Lachance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Patrizi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Lefebvre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela L.","family":"Follett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances E.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Volpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Vartanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2002,4,1]]},"reference":[{"key":"2023041302511123000_22.7.2478.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-04-01302.2001"},{"key":"2023041302511123000_22.7.2478.2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19980415)52:2<230::AID-JNR11>3.0.CO;2-B"},{"key":"2023041302511123000_22.7.2478.3","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1962.04210050022004"},{"key":"2023041302511123000_22.7.2478.4","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90531-G"},{"key":"2023041302511123000_22.7.2478.5","doi-asserted-by":"publisher","DOI":"10.1016\/0960-9822(93)90039-Q"},{"key":"2023041302511123000_22.7.2478.6","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/j.1471-0528.1998.tb09363.x","article-title":"Are neonatal brain lesions due to intrauterine infection related to mode of delivery?","volume":"105","author":"Baud","year":"1998","journal-title":"Br J Obstet Gynaecol"},{"key":"2023041302511123000_22.7.2478.7","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19960815)45:4<375::AID-JNR6>3.0.CO;2-6"},{"key":"2023041302511123000_22.7.2478.8","first-page":"71","article-title":"Cytokine circuits in brain. 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