title: Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns.
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.
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303.
authors.forename: Siddhartha Kumar
authors.initials: SK
authors.lastname: Bhaumik
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Yikun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Baumann
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia 30303, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department and Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Shang-Hsuan
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Imaging Research Center and.
authors.forename: R Scott
authors.identifier: http://orcid.org/0000-0001-8501-8290
authors.initials: RS
authors.lastname: Dunn
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267.
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institute, Miaoli County 35053, Taiwan.
authors.forename: Feng-Shiun
authors.initials: FS
authors.lastname: Shie
authors.affiliation: Department and Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, and.
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.affiliation: Divisions of Immunobiology and.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.affiliation: Neonatology/Pulmonary Biology, Cincinnati's Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
authors.affiliation: Divisions of Immunobiology and.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Lewkowich
authors.affiliation: Imaging Research Center and.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lindquist
authors.affiliation: 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.
authors.forename: Kaja
authors.initials: K
authors.lastname: Murali-Krishna
authors.affiliation: 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.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000188:drug therapy; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D002821:Chorioamnionitis / Q000188:drug therapy / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007231:Infant, Newborn; D007249:Inflammation / Q000517:prevention & control*; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D066127:White Matter / Q000187:drug effects
chemical_list: D016207:Cytokines; C515500:IL23R protein, human; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011409:Propylene Glycols; D018123:Receptors, Interleukin; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: FTY720; Fingolimod; Th17; adaptive immunity; chorioamnionitis; choroid plexus