Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns
| Autor: | Feng Shiun Shie, Claire A. Chougnet, Ian P. Lewkowich, Yi Hsuan Lee, Jessica M. Baumann, Diana M. Lindquist, Chia-Yi Kuan, Siddhartha Kumar Bhaumik, Shang Hsuan Lin, Chia-Yang Liu, Dianer Yang, Yu-Yo Sun, Yikun Li, Suhas G. Kallapur, R. Scott Dunn, Kaja Murali-Krishna, Marsha Wills-Karp, Yujin Zhang, Xiaoyi Lin |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Lipopolysaccharides
Lymphocyte T-Lymphocytes Inflammation Blood–brain barrier Systemic inflammation Chorioamnionitis Lymphocyte Activation Proinflammatory cytokine Cell Movement Pregnancy Sphingosine medicine Animals Humans Lymphocytes Microglia Dose-Response Relationship Drug business.industry Fingolimod Hydrochloride General Neuroscience Infant Newborn NF-kappa B Brain Articles Receptors Interleukin medicine.disease White Matter Rats medicine.anatomical_structure Animals Newborn Blood-Brain Barrier Propylene Glycols Immunology Hypoxia-Ischemia Brain Cytokines Choroid plexus Female medicine.symptom Atrophy business Immunosuppressive Agents |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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