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J Neurosci. 2014 Dec 3;34(49):16467-81. doi: 10.1523/JNEUROSCI.2582-14.2014.

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

Author information

1
Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
2
Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303.
3
Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267.
4
Department and Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan.
5
Imaging Research Center and.
6
Center for Neuropsychiatric Research, National Health Research Institute, Miaoli County 35053, Taiwan.
7
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, and.
8
Divisions of Immunobiology and.
9
Neonatology/Pulmonary Biology, Cincinnati's Children's Hospital Medical Center, Cincinnati, Ohio 45229.
10
Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, International Center for Genetic Engineering and Biotechnology (ICGEB)-Emory Vaccine Center, ICGEB, 100 067 New Delhi, India.
11
Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, alex.kuan@emory.edu.

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.

KEYWORDS:

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

PMID:
25471584
PMCID:
PMC4252554
DOI:
10.1523/JNEUROSCI.2582-14.2014
[Indexed for MEDLINE]
Free PMC Article

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