Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis

Ross C. Gruber, Alex K. Ray, Christopher T. Johndrow, Hillary Guzik, Dominika Burek, Pablo García De Frutos, Bridget Shafit-Zagardo

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Growth 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 Tyro3mRNA.Wetested 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 IFNb injection did not enhance GAS6 treatment effectiveness. Gas6-/-mice sensitized withMOG35-55peptide 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 proinflammatorymRNAmolecules, 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 thanWTspinal cords. Our data are consistent withGAS6being protective duringEAEby dampening the inflammatory response, thereby preserving axonal integrity and myelination.

Original languageEnglish (US)
Pages (from-to)16320-16335
Number of pages16
JournalJournal of Neuroscience
Volume34
Issue number49
DOIs
StatePublished - Dec 3 2014

Keywords

  • Demyelination
  • EAE
  • GAS6
  • Inflammation
  • Neuroprotection
  • TAM receptor

ASJC Scopus subject areas

  • Neuroscience(all)

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