{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T12:40:26Z","timestamp":1787056826167,"version":"build-2736575974"},"reference-count":55,"publisher":"Society for Neuroscience","issue":"49","license":[{"start":{"date-parts":[[2015,6,3]],"date-time":"2015-06-03T00:00:00Z","timestamp":1433289600000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2014,12,3]]},"abstract":"<jats:p>Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic\u2013ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (T<jats:sub>H<\/jats:sub>17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS\/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early T<jats:sub>H<\/jats:sub>17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS\/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-\u03baB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood\u2013brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing &gt;90% of LPS\/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the T<jats:sub>H<\/jats:sub>17\/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.<\/jats:p>","DOI":"10.1523\/jneurosci.2582-14.2014","type":"journal-article","created":{"date-parts":[[2014,12,3]],"date-time":"2014-12-03T19:04:16Z","timestamp":1417633456000},"page":"16467-16481","source":"Crossref","is-referenced-by-count":70,"title":["Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic\u2013Ischemic Brain Injury in Newborns"],"prefix":"10.1523","volume":"34","author":[{"given":"Dianer","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Yo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddhartha Kumar","family":"Bhaumik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang-Hsuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8501-8290","authenticated-orcid":false,"given":"R. 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