TL1A mediates fibroblast-like synoviocytes migration and Indian Hedgehog signaling pathway via TNFR2 in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joints inflammation. One of the aggressive characteristics of RA fibroblast-like synoviocytes (FLS) is the tendency for migration in the local environment, which plays a central role in the RA pathogenesis. Tumor Necrosis Factor (TNF)-like cytokine 1A (TL1A) is a member of TNF superfamily, which has a role in autoimmunity and influences the RA-FLS behavior through TNF receptor 2 (TNFR2). We investigated the effect of TNF-like cytokine 1A (TL1A) on RA-FLS migration using patients' samples. Specifically, we examined the hedgehog signaling pathway which is a key regulator in chondrocyte growth and differentiation. We found that TL1A increased significantly the hedgehog homologue Indian hedgehog (IHH) and its receptor Patched 1, 2 (PTCH 1, 2) in RA-FLS. In addition, TL1A-stimulated RAFLS promoted significantly IHH protein expression. However, both mRNA and protein levels decreased substantially after blocking TL1A with TNFR2 antagonist. The migratory property of RA-FLS was enhanced after stimulation of RA-FLS with TL1A, but was compromised following TL1A blockage. In conclusion, our study has revealed that TL1A modulated RA-FLS migration and Indian hedgehog signaling pathway using TNFR2.