Chronic inflammation plays an important role in the progression of osteoarthritis (OA). Cumulative evidence suggests that natural killer (NK) cells potentially participate in OA inflammation. To investigate the regulation of NK cell reactivity in OA synovium, we characterized the phenotypic and functional properties of infiltrating NK cells in the synovial tissue in a rat collagenase-induced OA model. Our data indicated that in comparison with splenic NK cells, OA synovial NK cells were poorly responsive to the stimulation of IL-12 plus IL-15 and IL-18, as evidenced by lower production of IFN-γ, perforin and granzyme B. Consistently, synovial NK cells showed lower cytotoxicity to target cells than splenic NK cells. Further investigations revealed that synovial NK cells highly expressed receptor activator of nuclear factor-κB (RANK), while OA synovial fibroblasts (SFs) upregulated the expression of RANK ligand (RANKL). Co-culture of OA SFs with RANK-expressing NK cells inhibited cytokine-induced production of above cytotoxic mediators in NK cells and subsequently impaired NK cell cytotoxicity. Gene silencing of RANKL expression in SFs partially recovered the cytotoxicity of NK cells after co-culture. Furthermore, through the RANKL-RANK axis, OA SFs induced RANKL expression in NK cells and subsequently promoted the osteoclastogenic activity of NK cells in vitro. Taken together, our study showed that OA SF inhibited the cytotoxicity while augmenting the osteoclastogenic activity of NK cells through the RANKL-RANK axis. This study reveals a novel mechanism by which SFs modulate the reactivity of synovial NK cells in OA.

中文翻译：

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滑膜成纤维细胞通过骨关节炎中的 RANKL-RANK 轴调节滑膜自然杀伤细胞的细胞毒性和破骨细胞活性

慢性炎症在骨关节炎 (OA) 的进展中起着重要作用。累积证据表明，自然杀伤 (NK) 细胞可能参与 OA 炎症。为了研究 OA 滑膜中 NK 细胞反应性的调节，我们表征了在大鼠胶原酶诱导的 OA 模型中浸润滑膜组织中 NK 细胞的表型和功能特性。我们的数据表明，与脾脏 NK 细胞相比，OA 滑膜 NK 细胞对 IL-12 加 IL-15 和 IL-18 的刺激反应较差，如 IFN-γ、穿孔素和颗粒酶 B 的产生较低所证明。一致，滑膜 NK 细胞对靶细胞的细胞毒性低于脾 NK 细胞。进一步的研究表明，滑膜 NK 细胞高表达核因子-κB 受体激活剂（RANK），而OA滑膜成纤维细胞（SFs）上调RANK配体（RANKL）的表达。OA SFs 与表达 RANK 的 NK 细胞的共培养抑制了细胞因子诱导的 NK 细胞中上述细胞毒性介质的产生，随后削弱了 NK 细胞的细胞毒性。SFs中RANKL表达的基因沉默部分恢复了共培养后NK细胞的细胞毒性。此外，通过 RANKL-RANK 轴，OA SFs 诱导 NK 细胞中的 RANKL 表达，随后在体外促进了 NK 细胞的破骨细胞活性。总之，我们的研究表明，OA SF 抑制了细胞毒性，同时通过 RANKL-RANK 轴增强了 NK 细胞的破骨细胞活性。这项研究揭示了一种新的机制，通过该机制，SFs 调节 OA 中滑膜 NK 细胞的反应性。