The effect and possible clinical efficacy of in vivo inhibition of neutrophil extracellular traps by blockade of PI3K-gamma on the pathogenesis of microscopic polyangiitis
The effect and possible clinical efficacy of in vivo inhibition of neutrophil extracellular traps by blockade of PI3K-gamma on the pathogenesis of microscopic polyangiitis
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DOI：
10.1080/14397595.2017.1367116
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发表时间：
2018-01-01
影响因子：
2.2
通讯作者：
Sasaki, Takehiko
中科院分区：
文献类型：
--
作者：
Kimura, Hirotaka;Matsuyama, Yasushi;Sasaki, Takehiko
目的：中性粒细胞胞外陷阱（Neutrophil extracellular traps，NET）是由活化的中性粒细胞以活性氧（reactive oxygen species，ROS）依赖的方式形成的一种特殊结构，由染色质和胞内蛋白质组成。异常NET被认为是抗中性粒细胞胞浆抗体（ANCA）的自身抗原，导致显微镜下多血管炎（MPA）的发生。然而，关于体内抑制NET形成（NETosis）对MPA发病机制的治疗功效知之甚少。本研究确定是否减少NETosis防止ANCA生产和改善特征involvement.Methods：MPA的小鼠模型诱导管理一种新的提取物从白色念珠菌设计。通过应用这种方法缺乏磷脂酰肌醇3-激酶γ（PI 3 K-γ），这是必不可少的活性氧在中性粒细胞的生产小鼠，我们调查了在体内NET，ANCA滴度和组织学damage.Results的水平：我们的模型表现出在体内NET的积累，升高ANCA滴度和特征性病理模仿人类MPA，包括小血管炎和新月体肾小球肾炎。引人注目的是，这些异常通过遗传和/或阻断PI 3 K-γ而减少。此外，药理PI 3 K-γ阻断降低了人类NETs的水平。结论：我们的研究结果表明，在体内抑制NETosis阻断PI 3 K-γ可能是一个有前途的治疗策略MPA的发病机制。
Objective: Neutrophil extracellular traps (NETs) are peculiar structures composed of the externalized chromatin with intracellular proteins and formed by activated neutrophils in a reactive oxygen species (ROS)-dependent manner. Aberrant NETs are considered to be autoantigens for anti-neutrophil cytoplasmic antibodies (ANCAs) underling the development of microscopic polyangiitis (MPA). However, little is known regarding the therapeutic efficacy of in vivo inhibition of NET formation (NETosis) on MPA pathogenesis. This study determines whether reducing NETosis prevents ANCA production and improves characteristic involvement.Methods: A mouse model of MPA induced by administering a novel extract from Candida albicans was devised. By applying this method to mice lacking phosphoinositide 3-kinase gamma (PI3K-gamma), which is indispensable for ROS production in neutrophils, we investigated the levels of in vivo NETs, ANCA titers and histological damage.Results: Our model exhibited accumulation of NETs in vivo, elevation of ANCA titers and characteristic pathologies mimicking human MPA, including small-vessel vasculitis and crescentic glomerulonephritis. Strikingly, these abnormalities were reduced by genetically and/or pharmacologically blocking PI3K-gamma. Moreover, a pharmacological PI3K-gamma blockade decreased the levels of human NETs.Conclusion: Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA.