Neutrophil extracellular traps promote differentiation and function of fibroblasts
Neutrophil extracellular traps promote differentiation and function of fibroblasts
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DOI：
10.1002/path.4359
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发表时间：
2014-07-01
影响因子：
7.3
通讯作者：
Kambas, Konstantinos
中科院分区：
文献类型：
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作者：
Chrysanthopoulou, Akrivi;Mitroulis, Ioannis;Kambas, Konstantinos
炎症刺激下的中性粒细胞活化和细胞外染色质结构（中性粒细胞胞外陷阱- nets）的释放与炎症性疾病有关。在此，我们证明中性粒细胞释放的NET可以通过纤维相关药物（如香烟烟雾、硅酸镁、博来霉素）或通用NET诱诱剂（如12-肉豆蔻酸酯13-乙酸佛波）诱导肺成纤维细胞（LFs）的激活并分化为肌成纤维细胞（MF）表型。有趣的是，上述药物或IL-17（炎症/纤维化的主要发起者）对LF激活和分化没有直接影响。经NETs处理的MFs显示结缔组织生长因子表达、胶原蛋白生成和增殖/迁移增加。用DNase1、肝素或髓过氧化物酶抑制剂降解NETs后，这些纤维化作用显著降低，表明net衍生成分在LF分化和功能中的关键作用。此外，IL-17在NETs中表达，并促进分化的LFs的纤维化活性，但不促进其分化，这表明DNA和组蛋白的启动对于IL-17驱动的纤维化至关重要。此外，自噬被确定为NET形成的协调者，正如使用巴菲霉素A1或wortmannin的抑制研究所显示的那样。在纤维化间质性肺病患者或皮肤瘢痕组织的活检中，在表达α -平滑肌肌动蛋白（-SMA）的成纤维细胞附近检测到NETs，进一步支持了上述发现。综上所述，这些数据表明，自噬和NETs不仅参与炎症，还参与随后的纤维化，因此可能代表了人类纤维化疾病的潜在治疗靶点。版权所有(c) 2014大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版
Neutrophil activation by inflammatory stimuli and the release of extracellular chromatin structures (neutrophil extracellular traps-NETs) have been implicated in inflammatory disorders. Herein, we demonstrate that NETs released by neutrophils treated either with fibrosis-related agents, such as cigarette smoke, magnesium silicate, bleomycin, or with generic NET inducers, such as phorbol 12-myristate 13-acetate, induced activation of lung fibroblasts (LFs) and differentiation into myofibroblast (MF) phenotype. Interestingly, the aforementioned agents or IL-17 (a primary initiator of inflammation/fibrosis) had no direct effect on LF activation and differentiation. MFs treated with NETs demonstrated increased connective tissue growth factor expression, collagen production, and proliferation/migration. These fibrotic effects were significantly decreased after degradation of NETs with DNase1, heparin or myeloperoxidase inhibitor, indicating the key role of NET-derived components in LF differentiation and function. Furthermore, IL-17 was expressed in NETs and promoted the fibrotic activity of differentiated LFs but not their differentiation, suggesting that priming by DNA and histones is essential for IL-17-driven fibrosis. Additionally, autophagy was identified as the orchestrator of NET formation, as shown by inhibition studies using bafilomycin A1 or wortmannin. The above findings were further supported by the detection of NETs in close proximity to alpha-smooth muscle actin (-SMA)-expressing fibroblasts in biopsies from patients with fibrotic interstitial lung disease or from skin scar tissue. Together, these data suggest that both autophagy and NETs are involved not only in inflammation but also in the ensuing fibrosis and thus may represent potential therapeutic targets in human fibrotic diseases. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd