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

• Published in: The Journal of neuroscience 2014-12, Vol.34 (49), p.16467-16481
• Main Authors: Yang, Dianer, Sun, Yu-Yo, Bhaumik, Siddhartha Kumar, Li, Yikun, Baumann, Jessica M, Lin, Xiaoyi, Zhang, Yujin, Lin, Shang-Hsuan, Dunn, R Scott, Liu, Chia-Yang, Shie, Feng-Shiun, Lee, Yi-Hsuan, Wills-Karp, Marsha, Chougnet, Claire A, Kallapur, Suhas G, Lewkowich, Ian P, Lindquist, Diana M, Murali-Krishna, Kaja, Kuan, Chia-Yi
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Atrophy - drug therapy; Blood-Brain Barrier - drug effects; Brain - drug effects; Brain - metabolism; Brain - pathology; Cell Movement - drug effects; Chorioamnionitis - drug therapy; Chorioamnionitis - metabolism; Cytokines - metabolism; Dose-Response Relationship, Drug; Female; Fingolimod Hydrochloride; Humans; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - pathology; Hypoxia-Ischemia, Brain - prevention & control; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Infant, Newborn; Inflammation - prevention & control; Lipopolysaccharides; Lymphocyte Activation - drug effects; Lymphocytes - cytology; Lymphocytes - drug effects; NF-kappa B - metabolism; Pregnancy; Propylene Glycols - pharmacology; Propylene Glycols - therapeutic use; Rats; Receptors, Interleukin - metabolism; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Sphingosine - therapeutic use; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; White Matter - drug effects
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2582-14.2014

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.