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

Journal of Neuroscience - Tập 34 Số 49 - Trang 16467-16481 - 2014
Dianer Yang1,2, Yu Sun1,2, Siddhartha Kumar Bhaumik1, Yikun Li1,2, Jessica M. Baumann1,2, Xiaoyi Lin1,2, Yujin Zhang3, Shang-Hsuan Lin4, Richard S. Dunn5, Chia‐Yang Liu3, Feng‐Shiun Shie6, Yi‐Hsuan Lee4, Marsha Wills‐Karp7, Claire Chougnet8, Suhas G. Kallapur9, Ian Lewkowich8, Diana M. Lindquist5, Kaja Murali‐Krishna10,1, Chia‐Yi Kuan1,2
11Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303,
22Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
33Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267,
44Department and Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan,
55Imaging Research Center and
68Center for Neuropsychiatric Research, National Health Research Institute, Miaoli County 35053, Taiwan,
79Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, and
86Divisions of Immunobiology and
97Neonatology/Pulmonary Biology, Cincinnati's Children's Hospital Medical Center, Cincinnati, Ohio 45229,
1010International Center for Genetic Engineering and Biotechnology (ICGEB)–Emory Vaccine Center, ICGEB, 100 067 New Delhi, India

Tóm tắt

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 bothin vivoandin vitromodels, 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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Journal of Neuroscience

Tập 34 Số 49

16467-16481

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