Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Ichihara Hospital, Tsukuba, Ibaraki 300-3295, Japan.
Int J Mol Sci. 2021 Jul 16;22(14):7633. doi: 10.3390/ijms22147633.
Neutrophils and their extracellular traps have been shown to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the detailed mechanisms in joints are still unclear, and their regulation remains to be solved. Here, we explored neutrophil extracellular trap (NET)osis in experimental models of arthritis and further investigated the effects of interleukin-6 (IL-6) inhibition in neutrophils and NETosis. In skins of peptide GPI-induced arthritis (pGIA), citrullinated protein was detected as well as citrullinated histone expression in immunized skin but this was not specific to pGIA. Citrullinated histone expression in pGIA joints was specific to pGIA and was merged with neutrophil elastase, suggesting NETosis. Neutrophils in joints tend to upregulate IL-6 receptors when compared with bone marrow neutrophils. Administration of mouse anti-IL-6 receptor antibodies in pGIA suppressed arthritis in association with a decrease in neutrophil infiltration and NETosis in joints. In the plasma of RA patients, citrullinated protein was significantly reduced after tocilizumab treatment. Our results suggest that IL-6 enhances neutrophil chemotaxis and NETosis in inflammatory joints and could be the source of citrullinated proteins.
中性粒细胞及其细胞外陷阱（NET）已被证明在类风湿关节炎（RA）的发病机制中发挥重要作用，但关节内的详细机制仍不清楚，其调控仍有待解决。在这里，我们研究了关节炎实验模型中的中性粒细胞细胞外陷阱（NET）形成，并进一步研究了白细胞介素-6（IL-6）在中性粒细胞和 NET 形成中的抑制作用。在肽 GPI 诱导的关节炎（pGIA）皮肤中，除了在免疫皮肤中检测到瓜氨酸化蛋白外，还检测到瓜氨酸化组蛋白的表达，但这并不特异于 pGIA。pGIA 关节中的瓜氨酸化组蛋白表达特异于 pGIA，并与中性粒细胞弹性蛋白酶融合，提示 NET 形成。与骨髓中性粒细胞相比，关节中的中性粒细胞更倾向于上调 IL-6 受体。在 pGIA 中给予抗鼠 IL-6 受体抗体可抑制关节炎，同时减少关节内中性粒细胞浸润和 NET 形成。在 RA 患者的血浆中，托珠单抗治疗后瓜氨酸化蛋白明显减少。我们的研究结果表明，IL-6 增强了炎症关节中中性粒细胞的趋化性和 NET 形成，并且可能是瓜氨酸化蛋白的来源。
