Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR–sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA.

类风湿性关节炎 (RA) 因 TNF-α 信号传导而恶化。然而，尚不清楚 TNF-α 激活的 TNFR1 和 TNFR2 是否受细胞外因子的调节。在这里，我们发现通过蛋白水解切割产生的可溶性糖基化白细胞介素 17 受体 D (sIL-17RD) 增强了 TNF-α 诱导的 RA。我们发现 IL-17RD 脱落是由蛋白水解酶 TACE 诱导的，并由巨噬细胞中 TNF-α 的表达增强。有趣的是，关节炎小鼠和大鼠的血清中 sIL-17RD 升高。重组 sIL-17RD 通过促进 TNF-α-TNFR-sIL-17RD 复合物形成和受体聚集显着增强 TNF-α 诱导的促炎反应，导致胶原诱导性关节炎的加速发展。我们的观察表明，IL-17RD 的胞外域脱落发生在 RA 中，以增强 TNF-α 诱导的炎症反应。靶向sIL-17RD可能为RA的治疗提供新的策略。