核穿透性抗DNA自身抗体对NETosis的抑制作用

Q3 Medicine
Xiaoyong Chen, B. Cuffari, V. Dubljevic, Anupama R Shirali, Jiangbing Zhou, James A. Campbell, Stephen C Suits, K. O’Sullivan, J. Hansen
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引用次数: 2

摘要

核穿透性抗DNA自身抗体作为递送剂和靶向DNA和DNA损伤反应(DDR)具有治疗潜力。此类Abs的衍生物已在遗传疾病的人体测试中取得进展,并正在为肿瘤学临床试验做准备。与中性粒细胞外陷阱(NETs)相关的DNA释放有助于免疫、炎症和多种疾病的病理生理学。DDR有助于NETs的机制,我们假设定位于活细胞核并抑制DNA修复的抗DNA自身抗体将抑制活化的中性粒细胞释放NETs。在目前的研究中,我们评估了干扰DDR的核穿透性抗DNA自身抗体对从C57BL/6小鼠中分离的活化的人粒细胞样分化的PLB-985细胞和中性粒细胞的DNA和NETs的去凝聚和释放的影响。用对照或自身抗体预处理的细胞对随后的NETosis刺激物(包括PMA和钙离子载体离子霉素)的反应通过DAPI和SYTOX Green染色、DNA释放的测量、通过蛋白质印迹分析组蛋白瓜氨酸化或通过免疫染色和共聚焦荧光显微镜观察NETs来评估。细胞的自身抗体处理产生了对NADPH氧化酶依赖性和非依赖性NETosis的显著抑制。这些发现确立了核穿透性抗DNA自身抗体作为中性粒细胞生物学调节剂的概念,有可能用于抑制NETosis的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of NETosis by a Nuclear-Penetrating Anti-DNA Autoantibody
Nuclear-penetrating anti-DNA autoantibodies have therapeutic potential as delivery agents and in targeting DNA and the DNA damage response (DDR). Derivatives of such Abs have advanced to human testing in genetic disease and are in preparation for oncology clinical trials. DNA release associated with neutrophil extracellular traps (NETs) contributes to immunity, inflammation, and the pathophysiology of multiple diseases. The DDR contributes to mechanisms of NETosis, and we hypothesize that anti-DNA autoantibodies that localize into live cell nuclei and inhibit DNA repair will suppress release of NETs by activated neutrophils. In the current study we evaluated the impact of a nuclear-penetrating anti-DNA autoantibody that interferes with the DDR on decondensation and release of DNA and NETs by activated human granulocyte-like differentiated PLB-985 cells and neutrophils isolated from C57BL/6 mice. The response of cells pretreated with control or autoantibody to subsequent stimulators of NETosis, including PMA and the calcium ionophore ionomycin, was evaluated by DAPI and SYTOX Green stains, measurement of DNA release, analysis of histone citrullination by Western blot, or visualization of NETs by immunostaining and confocal fluorescence microscopy. Autoantibody treatment of the cells yielded significant inhibition of NADPH oxidase–dependent and independent NETosis. These findings establish the concept of nuclear-penetrating anti-DNA autoantibodies as modulators of neutrophil biology with potential for use in strategies to suppress NETosis.
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来源期刊
CiteScore
3.70
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