title: Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis.
abstract: OBJECTIVE
  Hyperactivation of innate immunity by Toll-like receptors (TLRs) can contribute to the development of autoinflammatory or autoimmune diseases. This study evaluated the activation of Tyro3, Axl, Mer (TAM) receptors, physiologic negative regulators of TLRs, by their agonists, growth arrest-specific protein 6 (GAS-6) and protein S, in the prevention of collagen-induced arthritis (CIA).
  
  
  METHODS
  Adenoviruses overexpressing GAS-6 and protein S were injected intravenously or intraarticularly into mice during CIA. Splenic T helper cell subsets from intravenously injected mice were studied by flow cytometry, and the knee joints of mice injected intravenously and intraarticularly were assessed histologically. Synovium from mice injected intraarticularly was evaluated for cytokine and suppressor of cytokine signaling (SOCS) expression.
  
  
  RESULTS
  Protein S significantly reduced ankle joint swelling when overexpressed systemically. Further analysis of knee joints revealed a moderate reduction in pathologic changes in the joint and a significant reduction in the number of splenic Th1 cells when protein S was overexpressed systemically. Local overexpression of GAS-6 decreased joint inflammation and joint pathology. Protein S treatment showed a similar trend of protection. Consistently, GAS-6 and protein S reduced cytokine production in the synovium. Moreover, levels of messenger RNA for interleukin-12 (IL-12) and IL-23 were reduced by GAS-6 and protein S treatment, with a corresponding decrease in the production of interferon-γ and IL-17. TAM ligand overexpression was associated with an increase in SOCS-3 levels, which likely contributed to the amelioration of arthritis.
  
  
  CONCLUSIONS
  This study provides the first evidence that TAM receptor stimulation by GAS-6 and protein S can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and adaptive immunity. This pathway provides a novel strategy by which to combat rheumatoid arthritis.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: B T
authors.initials: BT
authors.lastname: van den Brand
authors.forename: S
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: E A
authors.initials: EA
authors.lastname: Vermeij
authors.forename: M B
authors.initials: MB
authors.lastname: Bennink
authors.forename: O J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: C V
authors.initials: CV
authors.lastname: Rothlin
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: F A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D007270:Injections, Intra-Articular; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D017293:Protein S / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C491411:Socs3 protein, mouse; C490767:Mertk protein, mouse; C513478:Tyro3 protein, mouse