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In this study, we investigated whether stroke damaged the blood\u2013CSF barrier integrity due to dysregulation of major ChP ion transport system, Na\n                      <jats:sup>+<\/jats:sup>\n                      \u2013K\n                      <jats:sup>+<\/jats:sup>\n                      \u2013Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      cotransporter 1 (NKCC1), and regulatory Ste20-related proline-alanine-rich kinase (SPAK).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Sham or ischemic stroke was induced in C57Bl\/6J mice. Changes on the SPAK\u2013NKCC1 complex and tight junction proteins (TJs) in the ChP were quantified by immunofluorescence staining and immunoblotting. Immune cell infiltration in the ChP was assessed by flow cytometry and immunostaining. Cultured ChP epithelium cells (CPECs) and cortical neurons were used to evaluate H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      -mediated oxidative stress in stimulating the SPAK\u2013NKCC1 complex and cellular damage. In vivo or in vitro pharmacological blockade of the ChP SPAK\u2013NKCC1 cascade with SPAK inhibitor ZT-1a or NKCC1 inhibitor bumetanide were examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ischemic stroke stimulated activation of the CPECs apical membrane SPAK\u2013NKCC1 complex, NF-\u03baB, and MMP9, which was associated with loss of the blood\u2013CSF barrier integrity and increased immune cell infiltration into the ChP. Oxidative stress directly activated the SPAK\u2013NKCC1 pathway and resulted in apoptosis, neurodegeneration, and NKCC1-mediated ion influx. Pharmacological blockade of the SPAK\u2013NKCC1 pathway protected the ChP barrier integrity, attenuated ChP immune cell infiltration or neuronal death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Stroke-induced pathological stimulation of the SPAK\u2013NKCC1 cascade caused CPECs damage and disruption of TJs at the blood\u2013CSF barrier. The ChP SPAK\u2013NKCC1 complex emerged as a therapeutic target for attenuating ChP dysfunction and lymphocyte invasion after stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-022-02456-4","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T17:02:55Z","timestamp":1649782975000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Role of SPAK\u2013NKCC1 signaling cascade in the choroid plexus blood\u2013CSF barrier damage after stroke"],"prefix":"10.1186","volume":"19","author":[{"given":"Jun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Nabiul","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Como","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria M.","family":"Fiesler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Iqbal H.","family":"Bhuiyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianming","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arohan R.","family":"Subramanya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulnaz","family":"Begum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,12]]},"reference":[{"issue":"8","key":"2456_CR1","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nrn3921","volume":"16","author":"MP Lun","year":"2015","unstructured":"Lun MP, Monuki ES, Lehtinen MK. 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