PhD Scientific Days 2025

Molecular Medicine I.

The effect of synovial fibroblast-specific tyrosine kinase deletion in a chronic polyarthritis model in mice

Name of the presenter

Majerhoffer Nóra

Institute/workplace of the presenter

Department of Physiology, Semmelweis University

Authors

Nóra Majerhoffer¹, Adrienn Bóka¹, Attila Mócsai¹, Tamás Németh¹

1: Department of Physiology, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction: Rheumatoid arthritis is characterized by synovitis and joint destruction, which is partly due to the activation of synovial fibroblasts (fibroblast-like synoviocytes, FLS). Although there are several therapies available, there are still a lot of patients, who do not respond well, meaning that we need to have new therapeutic options. The Abl and the Syk tyrosine kinases are important molecules in immune receptor and integrin signaling and have been proposed to have a role in FLS in vitro.
Aims: Here, we investigated the role of the Abl and the Syk tyrosine kinases in FLS in the development of a chronic experimental arthritis.
Methods: FLS-specific deletion of Abl and Syk was achieved by the Cre-Lox system (resulting in AblΔFLS and SykΔFLS mice). Lymphoid organs were isolated from OT-II transgenic mice and ovalbumin-specific CD4+ T cells were separated by MACS. After polarization into Th1 direction, T cells were injected into wild type, AblΔFLS or SykΔFLS mice, and animals were immunized with ovalbumin. Next, mice were challenged with the antigen in the hind limb and were rechallenged a few weeks later. Arthritis was followed by ankle thickness measurements and clinical scoring. Pannus formation was examined by histological analysis of the joint, local immune cell accumulation was measured by flow cytometry. Proinflammatory cytokine levels and antibody titers were detected by ELISA. The presence of bone erosions was examined by micro-CT.
Results: AblΔFLS mice developed severe arthritis, but SykΔFLS mice had a milder joint inflammation compared to the wild type animals. Pannus formation was less severe, immune cell accumulation and proinflammatory cytokine levels were also lower in SykΔFLS mice. Furthermore, FLS-specific Syk expression seemed to be important for the development of bone erosions and for the production of anti-ovalbumin antibodies.
Conclusions: Our results indicate that – in contrast to Abl – Syk expression in FLS is important for the development of experimental chronic arthritis. These data propose that Syk inhibition may have a beneficial effect in the treatment of human autoimmune arthritis.
Funding: This work was funded by the Hungarian National Research, Development and Innovation Office and the Lendület program of the Hungarian Academy of Sciences. Nóra Majerhoffer is a recipient of an SE 250+ Excellence PhD Scholarship.