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Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro\u2010inflammatory IL\u20101\u03b2 to induce cyclooxygenase\u20102 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic\u2010ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with \u201cA2\u201d reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation <jats:italic>in vitro<\/jats:italic>. Pharmacologic blockade with EP1\u2010specific inhibitors (ONO\u20108711, SC\u201051089), or genetic deficiency of <jats:italic>EP1<\/jats:italic> attenuated effects of PGE2. In an IL\u20101\u03b2\u2010induced model of NWMI, astrocytes also exhibit \u201cA2\u201d reactivity and induce COX2. Furthermore, <jats:italic>in vivo<\/jats:italic> inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop \u201cA2\u201d reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2\u2010PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.<\/jats:p>","DOI":"10.1002\/glia.23212","type":"journal-article","created":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T08:48:00Z","timestamp":1504169280000},"page":"2024-2037","source":"Crossref","is-referenced-by-count":124,"title":["Reactive astrocyte COX2\u2010PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3279-1495","authenticated-orcid":false,"given":"Lawrence R.","family":"Shiow","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Division of Neonatology"},{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Favrais","sequence":"additional","affiliation":[{"name":"INSERM U930, Universite Francois Rabelais Tours France"},{"name":"Neonatal intensive care unit, CHRU de Tours, Universite Francois Rabelais Tours France"},{"name":"PROTECT, INSERM, Universite Paris Diderot, Sorbonne Paris Cite Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-4116","authenticated-orcid":false,"given":"Lucas","family":"Schirmer","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco San Francisco California"},{"name":"Department of Neurology Klinikum rechts der Isar, Technical University of Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Laure","family":"Schang","sequence":"additional","affiliation":[{"name":"PROTECT, INSERM, Universite Paris Diderot, Sorbonne Paris Cite Paris France"},{"name":"PremUP, Universite Paris Diderot, Sorbonne Paris Cite Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cipriani","sequence":"additional","affiliation":[{"name":"PROTECT, INSERM, Universite Paris Diderot, Sorbonne Paris Cite Paris France"},{"name":"PremUP, Universite Paris Diderot, Sorbonne Paris Cite Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Andres","sequence":"additional","affiliation":[{"name":"INSERM U930, Universite Francois Rabelais Tours France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn N.","family":"Wright","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Nobuta","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobbi","family":"Fleiss","sequence":"additional","affiliation":[{"name":"PROTECT, INSERM, Universite Paris Diderot, Sorbonne Paris Cite Paris France"},{"name":"PremUP, Universite Paris Diderot, Sorbonne Paris Cite Paris France"},{"name":"Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering King's College London, King's Health Partners, St. Thomas Hospital London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Gressens","sequence":"additional","affiliation":[{"name":"PROTECT, INSERM, Universite Paris Diderot, Sorbonne Paris Cite Paris France"},{"name":"PremUP, Universite Paris Diderot, Sorbonne Paris Cite Paris France"},{"name":"Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering King's College London, King's Health Partners, St. Thomas Hospital London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Rowitch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Division of Neonatology"},{"name":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco San Francisco California"},{"name":"Department of Paediatrics and Wellcome Trust\u2010MRC Stem Cell Institute, Cambridge University Cambridge United 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