Kimura Hirotaka, Matsuyama Yasushi, Araki Sachiko, Koizumi Atsushi, Kariya Yumi, Takasuga Shunsuke, Eguchi Satoshi, Nakanishi Hiroki, Sasaki Junko, Sasaki Takehiko
a Department of Medical Biology , Akita University Graduate School of Medicine , Akita , Japan.
b Research Center for Biosignaling , Akita University , Akita , Japan.
Mod Rheumatol. 2018 May;28(3):530-541. doi: 10.1080/14397595.2017.1367116. Epub 2017 Sep 7.
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.
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.
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.
Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA.
中性粒细胞胞外诱捕网（NETs）是由外化染色质与细胞内蛋白质组成的特殊结构，由活化的中性粒细胞以活性氧（ROS）依赖的方式形成。异常的NETs被认为是抗中性粒细胞胞浆抗体（ANCA）的自身抗原，是显微镜下多血管炎（MPA）发病的基础。然而，关于体内抑制NET形成（NETosis）对MPA发病机制的治疗效果知之甚少。本研究确定减少NETosis是否能预防ANCA产生并改善特征性病变。
设计了一种通过给予白色念珠菌新提取物诱导MPA的小鼠模型。通过将该方法应用于缺乏磷酸肌醇3激酶γ（PI3K-γ）的小鼠，PI3K-γ对中性粒细胞中ROS的产生必不可少，我们研究了体内NETs水平、ANCA滴度和组织学损伤。
我们的模型在体内表现出NETs的积累、ANCA滴度的升高以及模仿人类MPA的特征性病理变化，包括小血管血管炎和新月形肾小球肾炎。令人惊讶的是，通过基因和/或药理学方法阻断PI3K-γ可减少这些异常。此外，药理学上阻断PI3K-γ可降低人NETs水平。
我们的结果表明，通过阻断PI3K-γ在体内抑制NETosis可能是一种有前景的治疗MPA发病机制的策略。
