Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns

Dianer Yang, Yu Yo Sun, Siddhartha Kumar Bhaumik, Yikun Li, Jessica M. Baumann, Xiaoyi Lin, Yujin Zhang, Shang Hsuan Lin, R. Scott Dunn, Chia Yang Liu, Feng Shiun Shie, Yi Hsuan Lee, Marsha Wills-Karp, Claire A. Chougnet, Suhas G. Kallapur, Ian P. Lewkowich, Diana M. Lindquist, Kaja Murali-Krishna, Chia Yi Kuan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)16467-16481
Number of pages15
JournalJournal of Neuroscience
Volume34
Issue number49
DOIs
StatePublished - Dec 3 2014

Keywords

  • Adaptive immunity
  • Chorioamnionitis
  • Choroid plexus
  • FTY720
  • Fingolimod
  • Th17

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Yang, D., Sun, Y. Y., Bhaumik, S. K., Li, Y., Baumann, J. M., Lin, X., Zhang, Y., Lin, S. H., Dunn, R. S., Liu, C. Y., Shie, F. S., Lee, Y. H., Wills-Karp, M., Chougnet, C. A., Kallapur, S. G., Lewkowich, I. P., Lindquist, D. M., Murali-Krishna, K., & Kuan, C. Y. (2014). Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns. Journal of Neuroscience, 34(49), 16467-16481. https://doi.org/10.1523/JNEUROSCI.2582-14.2014