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Articles, Neurobiology of Disease

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 and Chia-Yi Kuan
Journal of Neuroscience 3 December 2014, 34 (49) 16467-16481; DOI: https://doi.org/10.1523/JNEUROSCI.2582-14.2014
Dianer Yang
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
2Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Yu-Yo Sun
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
2Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Siddhartha Kumar Bhaumik
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
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Yikun Li
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
2Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Jessica M. Baumann
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
2Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Xiaoyi Lin
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
2Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Yujin Zhang
3Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267,
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Shang-Hsuan Lin
4Department and Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan,
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R. Scott Dunn
5Imaging Research Center and
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  • ORCID record for R. Scott Dunn
Chia-Yang Liu
3Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267,
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Feng-Shiun Shie
8Center for Neuropsychiatric Research, National Health Research Institute, Miaoli County 35053, Taiwan,
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Yi-Hsuan Lee
4Department and Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan,
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Marsha Wills-Karp
9Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, and
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Claire A. Chougnet
6Divisions of Immunobiology and
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Suhas G. Kallapur
7Neonatology/Pulmonary Biology, Cincinnati's Children's Hospital Medical Center, Cincinnati, Ohio 45229,
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Ian P. Lewkowich
6Divisions of Immunobiology and
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Diana M. Lindquist
5Imaging Research Center and
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Kaja Murali-Krishna
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
10International Center for Genetic Engineering and Biotechnology (ICGEB)–Emory Vaccine Center, ICGEB, 100 067 New Delhi, India
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Chia-Yi Kuan
1Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
2Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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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.

  • adaptive immunity
  • chorioamnionitis
  • choroid plexus
  • Fingolimod
  • FTY720
  • Th17
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The Journal of Neuroscience: 34 (49)
Journal of Neuroscience
Vol. 34, Issue 49
3 Dec 2014
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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
Journal of Neuroscience 3 December 2014, 34 (49) 16467-16481; DOI: 10.1523/JNEUROSCI.2582-14.2014

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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
Journal of Neuroscience 3 December 2014, 34 (49) 16467-16481; DOI: 10.1523/JNEUROSCI.2582-14.2014
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Keywords

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

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