title: Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis.
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 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 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 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.
authors.affiliation: Department of Pathology.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Gruber
authors.affiliation: Department of Pathology.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Ray
authors.affiliation: Department of Microbiology and Immunology, and.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Johndrow
authors.affiliation: Analytical Imaging Facility, Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, Jack and Pearl Resnick Campus, Bronx, New York 10461, and.
authors.forename: Hillary
authors.initials: H
authors.lastname: Guzik
authors.affiliation: Department of Pathology.
authors.forename: Dominika
authors.initials: D
authors.lastname: Burek
authors.affiliation: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona, Barcelona 08036, Spain.
authors.forename: Pablo García
authors.initials: PG
authors.lastname: de Frutos
authors.affiliation: Department of Pathology, Bridget.Shafit-Zagardo@einstein.yu.edu.
authors.forename: Bridget
authors.initials: B
authors.lastname: Shafit-Zagardo
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D003711:Demyelinating Diseases / Q000188:drug therapy*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D057967:Infusions, Intraventricular; D007279:Injections, Subcutaneous; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009836:Oligodendroglia / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016899:Interferon-beta; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6
keywords: EAE; GAS6; TAM receptor; demyelination; inflammation; neuroprotection