TAMing inflammation and enhancing myelination in mouse models of multiple sclerosis

International Congress on Neuroimmunology and Therapeutics

DoubleTree by Hilton Hotel San Francisco Airport, San Francisco, CA, USA

Shafit-Zagardo B, Gruber RC, Ray AK, Johndrow CT and García de Frutos P

Posters-Accepted Abstracts: J Neurol Disord

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), wildtype (WT) mice demonstrate a significant induction of Gas6, Axl, and Mertk but not Pros1 or Tyro3 mRNA. We tested the hypothesis that intracerebroventricular (ICV) 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 cerebrospinal fluid (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 days had preserved SMI31+ neurofilament immunoreactivity, significantly fewer SMI32+ axonal swellings and spheroids, and less demyelination relative to ACSF-treated mice. Alternateday subcutaneous interferon-beta (IFNβ) 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, Iba1+ microglia/macrophages, and enhanced expression of several proinflammatory mRNA molecules, and decreased expression of early oligodendrocyte maturation markers relative to WT mouse spinal cords with scores for eight 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 is consistent with GAS6 being protective during EAE by dampening the inflammatory response, thereby preserving axonal integrity and myelination. Ongoing studies are examining targeted therapies to efficiently introduce Gas6 into the CNS.