Rac和Pak信号在嗜中性粒细胞胞外陷阱（NETs）形成中的关键作用定义了一个新的潜在治疗靶点。,American Journal of Hematology - X-MOL

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Rac和Pak信号在嗜中性粒细胞胞外陷阱（NETs）形成中的关键作用定义了一个新的潜在治疗靶点。
American Journal of Hematology ( IF 10.1 ) Pub Date : 2017-11-11 , DOI: 10.1002/ajh.24970
Mathilde Gavillet _{1,

2} , Kimberly Martinod _{3,

4} , Raffaele Renella _{1,

5} , Denisa D Wagner _{1,

3} , David A Williams _{1,

6}

Affiliation

小鼠中的NET形成（NETosis）由NADPH氧化酶产生的活性氧（ROS）产生和肽酰精氨酸脱亚氨酶4（PAD4）产生的组蛋白超瓜氨酸化得到支持。在多形核中性粒细胞（PMN）中表达的Rac1和Rac2调节细胞骨架，细胞形状，粘附和迁移，并且也是NADPH氧化酶复合物的重要组成部分。我们旨在使用先前描述的基于流式细胞仪的方法，探索Rac信号通路对上游鸟嘌呤交换因子（GEF）激活剂Vav和下游效应子p21激活的激酶Pak在PMNs NETosis中的作用。分析。Rac2-/-PMNs的瓜氨酸化组蛋白H3（H3Cit）阳性细胞水平降低，NETosis缺陷。Rac1Δ/Δ; 与单独删除Rac2相比，Rac2-/-PMNs表现出PMA诱导的H3Cit水平的进一步降低和对NETosis的更严重损害，表明这两个高度相关的蛋白具有重叠的作用。Vav1或Vav2的基因敲除并未损害H3Cit对佛波醇肉豆蔻酸酯（PMA）或NETosis的反应。结合在一起，Vav1和Vav3缺失会降低H3Cit反应，并引起适度但严重的NETosis损害。两种具有不同作用机理的抑制剂对Pak的药理抑制作用导致PMA刺激后H3Cit水平降低，并显着抑制NETosis。我们使用Pak2Δ/ΔPMNs验证了Pak的重要性，这表明组蛋白H3瓜氨酸化和NETosis明显受损。这些数据证实并更全面地定义了Rac信号通路在PMN NETosis中的关键作用。Rac信号级联反应可能代表抑制NETosis和相关病理过程的重要目标。

"点击查看英文标题和摘要"

A key role for Rac and Pak signaling in neutrophil extracellular traps (NETs) formation defines a new potential therapeutic target.

NET formation in mice (NETosis) is supported by reactive oxygen species (ROS) production by NADPH oxidase and histone hypercitrullination by peptidylarginine deiminase 4 (PAD4). Rac1 and Rac2, expressed in polymorphonuclear neutrophils (PMNs), regulate the cytoskeleton, cell shape, adhesion, and migration and are also essential components of the NADPH oxidase complex. We aimed to explore the role of the Rac signaling pathway including the upstream guanosine exchange factor (GEF) activator, Vav, and a downstream effector, the p21-activated kinase, Pak, on NETosis in PMNs using a previously described flow-cytometry-based assay. Rac2-/- PMNs showed reduced levels of citrullinated histone H3 (H3Cit)-positive cells and defective NETosis. Rac1Δ/Δ ; Rac2-/- PMNs demonstrated a further reduction in PMA-induced H3Cit levels and a more profound impairment of NETosis than deletion of Rac2 alone, suggesting an overlapping role of these two highly related proteins. Genetic knockouts of Vav1, or Vav2, did not impair H3Cit response to phorbol myristate ester (PMA) or NETosis. Combined, Vav1 and Vav3 deletions decreased H3Cit response and caused a modest but significant impairment of NETosis. Pharmacologic inhibition of Pak by two inhibitors with distinct mechanisms of action, led to reduced H3Cit levels after PMA stimulation, as well as significant inhibition of NETosis. We validated the importance of Pak using Pak2Δ/Δ PMNs, which demonstrated significantly impaired histone H3 citrullination and NETosis. These data confirm and more comprehensively define the key role of the Rac signaling pathway in PMN NETosis. The Rac signaling cascade may represent a valuable target for inhibition of NETosis and related pathological processes.

更新日期：2019-11-01

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