Dr. Rothlin is founder of Xetrios Therapeutics and is inventor on patents for TAM activators and ligands for the inhibition of inflammation.
Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis
Article first published online: 25 FEB 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 3, pages 671–680, March 2013
How to Cite
van den Brand, B. T., Abdollahi-Roodsaz, S., Vermeij, E. A., Bennink, M. B., Arntz, O. J., Rothlin, C. V., van den Berg, W. B. and van de Loo, F. A. J. (2013), Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis. Arthritis & Rheumatism, 65: 671–680. doi: 10.1002/art.37786
- Issue published online: 25 FEB 2013
- Article first published online: 25 FEB 2013
- Accepted manuscript online: 30 NOV 2012 04:06PM EST
- Manuscript Accepted: 30 OCT 2012
- Manuscript Received: 3 JUL 2012
- Top Institute Pharma. Grant Number: Project D1-101-0
- The Netherlands Organization for Scientific Research. Grant Number: Vidi grant 917.46.363
- Innovative Medicines Initiative. Grant Number: BTCure grant 115142-2
- NIH. Grant Number: R01-AI-089824
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).
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.
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.
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.