title: Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS) lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.
  
  
  METHODS
  WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays.
  
  
  RESULTS
  Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+) were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals.
  
  
  CONCLUSIONS
  These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data provide further support that administration of the Axl ligand Gas6 could be therapeutic for immune-mediated demyelinating diseases.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Weinger
authors.forename: Celia F
authors.initials: CF
authors.lastname: Brosnan
authors.forename: Olivier
authors.initials: O
authors.lastname: Loudig
authors.forename: Michael F
authors.initials: MF
authors.lastname: Goldberg
authors.forename: Fernando
authors.initials: F
authors.lastname: Macian
authors.forename: Heather A
authors.initials: HA
authors.lastname: Arnett
authors.forename: Anne L
authors.initials: AL
authors.lastname: Prieto
authors.forename: Vladislav
authors.initials: V
authors.lastname: Tsiperson
authors.forename: Bridget
authors.initials: B
authors.lastname: Shafit-Zagardo
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D006023:Glycoproteins / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000276:immunology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse