C-type lectin-like receptor 2 in platelets amplifies inflammation in rheumatoid arthritis

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2025-03-01 DOI:10.1016/j.rpth.2025.102866

Tomoyuki Sasaki , Ewelina Golebiewska , Toshiaki Shirai , Nagaharu Tsukiji , Kensuke Koyama , Shogo Tamura , Shimon Otake , Makoto Osada , Hirotaka Haro , Yukio Ozaki , Katsue Suzuki–Inoue

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Abstract

Background

Platelets play a crucial role not only in thrombosis and hemostasis but also in inflammation, including rheumatoid arthritis. Although synovial cells in the joints express the membrane protein podoplanin, and platelets express the podoplanin receptor C-type lectin-like receptor 2 (CLEC-2), the role of CLEC-2 in arthritis has not been elucidated.

Objectives

This study investigated the role of CLEC-2 in arthritis.

Methods

Fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis were cocultured with washed human platelets, activated platelet supernatants, or recombinant CLEC-2 (rCLEC-2) to assess FLS proliferation and inflammatory cytokine mRNA levels. A KRN/B6xNOD (K/BxN) mice serum-transfer arthritis (STA) mouse model was used to study the in vivo roles of CLEC-2/podoplanin. Radiation bone marrow chimeric mice were generated by transplanting fetal liver cells from platelet/megakaryocyte-specific CLEC-2 conditional knockout (cKO) or wild-type (WT) embryos, to which serum from K/BxN was transferred. Arthritis was assessed by measuring the thicknesses of all 4 limbs.

Results

Coculture with platelets or rCLEC-2 significantly enhanced FLS proliferation and increased the mRNA levels of inflammatory cytokines including IL-6, IL-8, CXCL-2, CXCL-3, IL-1β, and tumour necrosis factor-α. Furthermore, platelets from wild-type mice showed increased mRNA levels of these cytokines in mouse FLSs. CLEC-2–deficient platelets partially, but significantly, inhibited this effect. In the STA model, CLEC-2 cKO mice showed reduced arthritis compared to WT mice. Immunohistological analysis confirmed the presence of platelets in the proliferative synovium.

Conclusion

CLEC-2 amplified arthritic platelets by stimulating the production of inflammatory cytokines and cell proliferation in FLSs.

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血小板中的c型凝集素样受体2可放大类风湿关节炎的炎症

血小板不仅在血栓形成和止血中起着至关重要的作用，而且在炎症（包括类风湿关节炎）中也起着重要作用。虽然关节滑膜细胞表达膜蛋白podoplanin，血小板表达podoplanin受体c型凝集素样受体2 (CLEC-2)，但CLEC-2在关节炎中的作用尚未阐明。目的探讨CLEC-2在关节炎中的作用。方法将类风湿性关节炎患者的成纤维细胞样滑膜细胞（FLSs）与洗净的人血小板、活化的血小板上清或重组CLEC-2 （rCLEC-2）共培养，评估FLS的增殖和炎症细胞因子mRNA水平。采用KRN/B6xNOD （K/BxN）小鼠血清转移性关节炎（STA）小鼠模型，研究CLEC-2/podoplanin在体内的作用。通过移植血小板/巨核细胞特异性CLEC-2条件敲除（cKO）或野生型（WT）胚胎的胎儿肝细胞，将K/BxN的血清转移到其上，产生辐射骨髓嵌合小鼠。通过测量所有四肢的厚度来评估关节炎。结果血小板或rCLEC-2培养可显著增强FLS的增殖能力，并增加炎性细胞因子IL-6、IL-8、CXCL-2、CXCL-3、IL-1β和肿瘤坏死因子-α的mRNA水平。此外，野生型小鼠的血小板在小鼠FLSs中显示这些细胞因子的mRNA水平升高。缺乏clec -2的血小板部分但显著地抑制了这种作用。在STA模型中，与WT小鼠相比，CLEC-2 cKO小鼠显示关节炎减轻。免疫组织学分析证实在增生性滑膜中存在血小板。结论clec -2通过刺激炎性细胞因子的产生和细胞增殖来扩增关节炎血小板。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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