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Author Notes:

Email Address: Dr. Chia-Yi Kuan : alex.kuan@emory.edu

Y.-H.L., M.W.-K., C.A.C., S.G.K., I.P.L., D.M.L., M.-W.K., and C.-Y.K. designed research.

D.Y., Y.-Y.S., S.K.B., Y.L., J.M.B., X.L., Y.Z., S.-H.L., R.S.D., C.-Y.L., I.P.L., and D.M.L. performed research.

F.-S.S., C.A.C., and S.G.K. contributed unpublished reagents/analytic tools

D.Y., Y.-Y.S., S.K.B., Y.L., J.M.B., X.L., Y.Z., S.-H.L., R.S.D., C.-Y.L., Y.-H.L., M.W.-K., I.P.L., D.M.L., and M.-W.K. analyzed data; Y.-Y.S. and C.-Y.K. wrote the paper.

We thank Dr. Allan Jobe for providing preterm neonate cord blood samples and Casey Wells for isolation and freezing of mononuclear cells.

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Research Funding:

This study was supported in part by National Institutes of Health Grant NS074559 and a Children's Healthcare of Atlanta Trustee grant (C.-Y.K.)

Keywords:

  • adaptive immunity
  • chorioamnionitis
  • choroid plexus
  • Fingolimod
  • FTY720
  • Th17

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic-Ischemic Brain Injury in Newborns

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Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 34, Number 49

Publisher:

, Pages 16467-16481

Type of Work:

Article | Final Publisher PDF

Abstract:

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (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 (TH17)-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 TH17 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-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain 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 >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro 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 TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.

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© 2014 the authors

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