白细胞介素-17 受体 D 的可脱落可溶性形式通过促进 TNF-α 依赖性受体聚集加重胶原诱导性关节炎。
A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthritis through facilitating TNF-α-dependent receptor clustering.
机构信息
State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China.
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, China.
出版信息
Cell Mol Immunol. 2021 Aug;18(8):1883-1895. doi: 10.1038/s41423-020-00548-w. Epub 2020 Sep 22.
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.
类风湿关节炎（RA）是由 TNF-α 信号转导加剧的。然而，目前尚不清楚 TNF-α 激活的 TNFR1 和 TNFR2 是否受到细胞外因素的调节。在这里，我们表明，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。我们揭示了 IL-17RD 的脱落是由蛋白水解酶 TACE 诱导的，并被巨噬细胞中 TNF-α 的表达所增强。有趣的是，关节炎小鼠和大鼠的血清中 sIL-17RD 水平升高。重组 sIL-17RD 通过促进 TNF-α-TNFR-sIL-17RD 复合物的形成和受体聚集，显著增强了 TNF-α 诱导的促炎反应，从而加速了胶原诱导性关节炎的发展。我们的观察结果表明，在 RA 中发生了 IL-17RD 的胞外结构域脱落，以增强 TNF-α 诱导的炎症反应。靶向 sIL-17RD 可能为 RA 的治疗提供一种新策略。
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