Tyro3, Axl, MerTK-Receptor Activation by Gas6 or Pros1 Gene Delivery, ameliorates Collagen-induced arthritis

Fons A.J. van de Loo¹, Ben T. van Den Brand², Shahla Abdollahi-Roodsaz³, Eline A. Vermeij⁴, Miranda B. Bennink⁴, Onno J. Arntz⁵ and Wim B. van den Berg⁶, ¹Rheumatology Research & Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ²Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ³Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ⁴Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ⁵Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Nijmegen, Netherlands, ⁶Experimental Rheumatology (272), Radboud university medical center, Nijmegen, Netherlands

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: cytokines and synovitis, T cells

Session Information

Title: Cytokines, Mediators, and Gene Regulation

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Insufficient controlled activation of innate immunity by cytokines and pattern recognition receptors could develop into auto-immune diseases. Stimulation of dendritic cells via the Axl receptor in conjunction with IFNAR leads to upregulation of suppressor of cytokine signaling (SOCS) proteins 1 and 3 and broadly inhibit both Toll-like Receptor (TLR) signaling and TLR-induced cytokine-receptor cascades (Rothlin et al. Cell 2007). This study evaluated whether Tyro3 Axl MerTK (TAM)- receptor stimulation by Growth arrest specific 6 (Gas6) and Protein S (Pros1) as natural negative feedback for Toll-Like Receptor and cytokine signaling can be used to treat collagen-induced arthritis.

Methods:

Adenoviruses (1x10E7 FFU) overexpressing Gas6 and Pros1 were injected intravenously (i.v.) or 3x10E8 FFU intra-articularly (i.a.) into mice before onset of collagen-induced arthritis. Splenic T-helper subsets of intravenously injected were studied by flow cytometry and knee joints of mice injected i.v. and i.a. were assessed histologically. Messenger RNA expression was analyzed in synovium of i.a. injected mice. Ciruclating cytokines were measured on a Luminex-100 System (Luminex corp.) using a magnetic bead-based multiplex immunoassay (Milliplex, Merck Millipore). Joint inflammation was imaged using the ProSense probe with the IVIS Lumina (Caliper Life Sciences), using the Cy5.5 filter.

Results:

Gas6 or Pros1 did not affect arthritis incidence in either IV or IA injected animals. However, Pros1 did significantly reduce ankle joint swelling, and circulating levels of KC and IL-6. Histological analysis of knee joints revealed a moderate reduction of joint pathology and a significant reduction of splenic T-helper 1 cells when Pros1 was overexpressed systemically. Local overexpression of Gas6 decreased joint inflammation (as assessd histologically or imaged by ProSense) and joint pathology. Pros1 treatment showed a similar trend of protection. Consistently, Gas6 and Pros1 markedly reduced cytokine (IL-1β, IL-6, and TNFα) production in synovium. Moreover, IL-12 and IL-23 mRNA levels were reduced by Gas6 and Pros1, corresponding to a decrease in IFNγ and IL-17 production in synovium.

Conclusion:

We provide the first evidence that TAM receptor stimulation by Gas6 and Pros1 can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and the adaptive immunity. This pathway provides a novel strategy to combat rheumatoid arthritis.

Disclosure:

F. A. J. van de Loo,
None;

B. T. van Den Brand,
None;

S. Abdollahi-Roodsaz,
None;

E. A. Vermeij,
None;

M. B. Bennink,
None;

O. J. Arntz,
None;

W. B. van den Berg,
None.

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