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Targeted GAS6 Delivery to the CNS Protects Axons from Damage during Experimental Autoimmune Encephalomyelitis

AutorGruber, Ross C.; Ray, Alex K.; Johndrow, Christopher T.; Guzik, Hillary M.; Burek, Dominika; García de Frutos, Pablo ; Shaft-Zagardo, Bridget
Palabras claveDemyelination
EAE
GAS6
Neuroprotection
TAM receptor
Fecha de publicación3-dic-2014
EditorSociety for Neuroscience
CitaciónJournal of Neuroscience 34(49): 16320-16335 (2014)
ResumenGrowth arrest-specific protein 6 (GAS6) is a soluble agonist of the TYRO3, AXL, MERTK (TAM) family of receptor tyrosine kinases identified to have anti-inflammatory, neuroprotective, and promyelinating properties. During experimental autoimmune encephalomyelitis (EAE), wild-type (WT) mice demonstrate a significant induction of Gas6, Axl, and Mertk but not Pros1 or Tyro3 mRNA. We tested the hypothesis that intracerebroventricular delivery of GAS6 directly into the CNS of WT mice during myelin oligodendrocyte glycoprotein (MOG)-induced EAE would improve the clinical course of disease relative to artificial CSF (ACSF)-treated mice. GAS6 did not delay disease onset, but significantly reduced the clinical scores during peak and chronic EAE. Mice receiving GAS6 for 28 d had preserved SMI31(+) neurofilament immunoreactivity, significantly fewer SMI32(+) axonal swellings and spheroids and less demyelination relative to ACSF-treated mice. Alternate-day subcutaneous IFNß injection did not enhance GAS6 treatment effectiveness. Gas6(-/-) mice sensitized with MOG35-55 peptide exhibit higher clinical scores during late peak to early chronic disease, with significantly increased SMI32(+) axonal swellings and Iba1(+) microglia/macrophages, enhanced expression of several proinflammatory mRNA molecules, and decreased expression of early oligodendrocyte maturation markers relative to WT mouse spinal cords with scores for 8 consecutive days. During acute EAE, flow cytometry showed significantly more macrophages but not T-cell infiltrates in Gas6(-/-) spinal cords than WT spinal cords. Our data are consistent with GAS6 being protective during EAE by dampening the inflammatory response, thereby preserving axonal integrity and myelination.
Versión del editorhttp://dx.doi.org/10.1523/JNEUROSCI.2449-14.2014
URIhttp://hdl.handle.net/10261/125001
DOI10.1523/JNEUROSCI.2449-14.2014
Identificadoresdoi: 10.1523/JNEUROSCI.2449-14.2014
issn: 0270-6474
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