Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia.
Medicine School of Tunis, University of Tunis-El Manar, Tunis, Tunisia.
Front Immunol. 2021 Jun 15;12:663683. doi: 10.3389/fimmu.2021.663683. eCollection 2021.
Tissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets.
The present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction .
The levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points.
Our data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1β, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5.
Wnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.
组织来源的成纤维细胞样滑膜细胞（td-FLS）是血管翳形成的关键因素，并且在类风湿关节炎（RA）中有助于关节破坏和炎症。Wnt 家族的几个成员，包括 Wnt5a，可能有助于 RA td-FLS 的激活，并且可以作为潜在的治疗靶点。
本研究旨在研究 RA td-FLS 及其潜在前体细胞（液源性（fd）FLS 和纤维细胞）中 Wnt5a 信号成分的表达。我们还研究了 Wnt5a 在 RA td-FLS 促炎活性中的作用，以及抑制剂 SFRP5 是否可以恢复 Wnt5a 诱导的滑膜功能障碍。
使用 qPCR 在基础条件下测定培养的 RA td-FLS、fd-FLS 和纤维细胞中 Wnt5a、SFRP5、Wnt5a 受体/共受体和 Wnt5a 促炎靶标的水平。在用 Wnt5a 和 SFRP5 刺激 RA td-FLS 不同时间点后，评估促炎分子的表达。
我们的数据表明，RA 患者的 td-FLS、fd-FLS 和纤维细胞表达相似水平的 Wnt5a 和一组 Wnt5a 受体/共受体。我们还证明，Wnt5a 刺激 RA td-FLS 中促炎靶标的表达，特别是 IL1β、IL8 和 IL6。在存在 SFRP5 的情况下，Wnt5a 诱导的炎症增强。此外，Wnt5a 单独和与 SFRP5 一起抑制 TCF4 的基因表达和经典共受体 LRP5 的蛋白水平。
在 RA td-FLS 中，SFRP5 并没有抑制而是增强了 Wnt5a 的促炎作用。这项研究强调了在存在 SFRP5 的情况下，仔细评估 Wnt5a 反应变化的重要性。
