Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain.
Unidad de Gestión Clínica Reumatología, Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain.
J Biomed Sci. 2020 Apr 17;27(1):54. doi: 10.1186/s12929-020-00634-1.
Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory form of arthritis in which tumor necrosis factor (TNF)-α, a potent inducer of inflammatory response and a key regulator of innate immunity and of Th1 immune responses, plays a central role. NETosis is a mechanism of innate immune defense that is involved in diverse rheumatology diseases. Nevertheless, spontaneous NETosis generation in r-axSpA, its association to disease pathogenesis, and the NETosis involvement on anti-TNF-α therapy's effects has never been explored.
Thirty r-axSpA patients and 32 healthy donors (HDs) were evaluated. Neutrophil extracellular trap (NET) formation, mediators of signal-transduction cascade required for NETosis induction and cell-free NETosis-derived products were quantified. An additional cohort of 15 r-axSpA patients treated with infliximab (IFX) for six months were further analyzed. In vitro studies were designed to assess the effects of IFX in NETosis generation and the inflammatory profile triggered.
Compared to HDs, neutrophils from r-axSpA patients displayed augmented spontaneous NET formation, elevated expression of NET-associated signaling components, nuclear peptidylarginine deiminase 4 translocation and increased citrullinated histone H3. Furthermore, patients exhibited altered circulating levels of cell-free NETosis-derived products (DNA, nucleosomes and elastase). Additional studies revealed that cell-free NETosis-derived products could be suitable biomarkers for distinguish r-axSpA patients from HDs. Correlation studies showed association between cell-free NETosis-derived products and clinical inflammatory parameters. Besides, nucleosomes displayed potential as a biomarker for discriminate patients according to disease activity. IFX therapy promoted a reduction in both NETosis generation and disease activity in r-axSpA patients. Mechanistic in vitro studies further unveiled the relevance of IFX in reducing NET release and normalizing the augmented inflammatory activities promoted by NETs in mononuclear cells.
This study reveals that NETosis is enhanced in r-axSpA patients and identifies the NETosis-derived products as potential disease activity biomarkers. In addition, the data suggests the potential role of NET generation analysis for assessment of therapeutic effectiveness in r-axSpA.
放射学轴性脊柱关节炎（r-axSpA）是一种慢性炎症性关节炎，其中肿瘤坏死因子（TNF）-α是炎症反应的有力诱导物，也是先天免疫和 Th1 免疫反应的关键调节剂，起着核心作用。细胞外陷阱（NET）是先天免疫防御的一种机制，与多种风湿病有关。然而，r-axSpA 中自发的 NET 生成、其与疾病发病机制的关联以及 NET 对抗 TNF-α治疗效果的影响从未被探索过。
评估了 30 名 r-axSpA 患者和 32 名健康供体（HDs）。定量测定中性粒细胞胞外诱捕（NET）形成、诱导 NET 形成所需的信号转导级联的介质以及无细胞 NET 衍生产物。对另外 15 名接受英夫利昔单抗（IFX）治疗六个月的 r-axSpA 患者进行了进一步分析。设计了体外研究来评估 IFX 对 NET 生成和触发的炎症谱的影响。
与 HDs 相比，r-axSpA 患者的中性粒细胞显示出增强的自发 NET 形成、NET 相关信号成分表达升高、核肽基精氨酸脱亚氨酶 4 易位和瓜氨酸化组蛋白 H3 增加。此外，患者表现出循环中无细胞 NET 衍生产物（DNA、核小体和弹性蛋白酶）水平改变。进一步的研究表明，无细胞 NET 衍生产物可作为区分 r-axSpA 患者和 HDs 的合适生物标志物。相关性研究表明，无细胞 NET 衍生产物与临床炎症参数之间存在关联。此外，核小体显示出作为根据疾病活动度区分患者的生物标志物的潜力。IFX 治疗可降低 r-axSpA 患者的 NET 生成和疾病活动度。体外机制研究进一步揭示了 IFX 在减少 NET 释放和正常化单核细胞中由 NET 引起的增强的炎症活性方面的相关性。
这项研究表明，NET 生成在 r-axSpA 患者中增强，并确定 NET 衍生产物作为潜在的疾病活动生物标志物。此外，数据表明 NET 生成分析在评估 r-axSpA 治疗效果方面具有潜在作用。
