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We investigated effects of selective deletion of microglial <jats:italic>Nhe1<\/jats:italic> in <jats:italic>Cx3cr1\u2010Cre<jats:sup>ER<\/jats:sup>;Nhe1<jats:sup>f\/f<\/jats:sup><\/jats:italic> mice on neuroinflammation and tissue repair after ischemic stroke. Infarct volume was similar in corn oil or tamoxifen (Tam)\u2010treated mice at 48\u00a0hr and 14\u00a0days post\u2010stroke. However, the Tam\u2010treated mice showed significantly higher survival rate and faster neurological function recovery during day 1\u201314 post\u2010stroke. Deletion of microglial <jats:italic>Nhe1<\/jats:italic> prevented the elevation of CD11b<jats:sup>+<\/jats:sup>\/CD45<jats:sup>low\u2010med<\/jats:sup> microglia in the ischemic hemisphere at day 3 post\u2010stroke, but stimulated expression of Ym1, CD68, TGF\u2010\u03b2, IL\u201010, decreased expression of CD86 and IL\u20101\u03b2, and reduced GFAP<jats:sup>+<\/jats:sup> reactive astrocytes. Moreover, at day 14 post\u2010stroke, enhanced white matter myelination was detected in the microglial <jats:italic>Nhe1<\/jats:italic> deleted mice. In comparison, neuronal <jats:italic>Nhe1<\/jats:italic>\u2010null mice (the <jats:italic>CamKII\u2010Cre<jats:sup>+\/\u2212<\/jats:sup>;Nhe1<jats:sup>f\/f<\/jats:sup><\/jats:italic> mice) showed a significant reduction in both acute and subacute infarct volume, along with increased survival rate and moderate neurological function recovery. However, these neuronal <jats:italic>Nhe1<\/jats:italic>\u2010null mice did not exhibit reduced activation of CD11b<jats:sup>+<\/jats:sup>\/CD45<jats:sup>low\u2010med<\/jats:sup> microglia or CD11b<jats:sup>+<\/jats:sup>\/CD45<jats:sup>hi<\/jats:sup> macrophages in the ischemic brains, and they exhibited no reductions in white matter lesions. Taken together, this study demonstrated that deletion of microglial and neuronal <jats:italic>Nhe1<\/jats:italic> had differential effects on ischemic brain damage. Microglial NHE1 is involved in pro\u2010inflammatory responses during post\u2010stroke brain tissue repair. In contrast, neuronal NHE1 activation is directly associated with the acute ischemic neuronal injury but not inflammation. Our study reveals that NHE1 protein is a potential therapeutic target critical for differential regulation of ischemic neuronal injury, demyelination and tissue repair.<\/jats:p>","DOI":"10.1002\/glia.23456","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T07:49:51Z","timestamp":1532504991000},"page":"2279-2298","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Selective role of Na<sup>+<\/sup>\/H<sup>+<\/sup> exchanger in <i>Cx3cr1<sup>+<\/sup><\/i> microglial activation, white matter demyelination, and post\u2010stroke function recovery"],"prefix":"10.1002","volume":"66","author":[{"given":"Shanshan","family":"Song","sequence":"first","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"},{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine Tianjin University of Traditional Chinese Medicine Tianjin, 300193 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria M.","family":"Pigott","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley M.","family":"Foley","sequence":"additional","affiliation":[{"name":"Animal Imaging Center, University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachana","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulnaz","family":"Begum","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yejie","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E.","family":"Carney","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh Pittsburgh Pennsylvania, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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