Neutrophil extracellular traps activate IL-8 and IL-1 expression in human bronchial epithelia
Neutrophil extracellular traps activate IL-8 and IL-1 expression in human bronchial epithelia
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DOI：
10.1152/ajplung.00144.2019
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发表时间：
2020-07-01
影响因子：
4.9
通讯作者：
Clancy, John Paul
中科院分区：
文献类型：
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作者：
Hudock, Kristin M.;Collins, Margaret S.;Clancy, John Paul
神经细胞外陷阱（NET）提供宿主防御，但可以有助于多种人类疾病的病理生物学。我们试图确定NET促进人类气道细胞炎症的程度和机制。将在空气-液体界面生长的原代正常人支气管上皮细胞（HBE）和野生型（wt）CFBE 410-细胞（表达wtCFTR）在体外暴露于来自无关健康志愿者的无细胞NET 18小时。通过Luminex测量顶端上清液中的细胞因子，并通过RNA测序评估对HBE转录组的影响。NET持续刺激来自多个供体的HBE分泌IL-8、TNF-α和IL-1 α，对其他细胞因子（IL-6. G-CSF和GM-CSF）。编码IL-1家族细胞因子，特别是IL-36亚家族成员的HBE RNA的表达在对NET的应答中增加。NET暴露在阿那白滞素[重组人IL-1受体拮抗剂（rhIL-1 RA）]的存在下抑制了NET诱导的IL-8和TNF-α蛋白以及IL-36 α RNA的变化。rhIL-36 RA限制了暴露于NET的HBE中促炎细胞因子RNA表达的增加。NET选择性地上调HBE中的IL-1家族细胞因子应答，这增强了IL-8的产生并受到rhIL-1 RA的限制。目前的研究结果描述了一种独特的机制，通过这种机制，NET可能有助于体内人类肺部疾病的炎症。NET驱动的IL-1信号转导可能代表了一种新的靶点，用于调节以大量NET负荷为特征的疾病中的炎症。
Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro. Cytokines were measured in the apical supernatant by Luminex, and the effect on the HBE transcriptome was assessed by RNA sequencing. NETs consistently stimulated IL-8, TNF-alpha, and IL-1 alpha secretion by HBEs from multiple donors, with variable effects on other cytokines (IL-6. G-CSF, and GM-CSF). Expression of HBE RNAs encoding IL-1 family cytokines, particularly IL-36 subfamily members, was increased in response to NETs. NET exposure in the presence of anakinra [recombinant human IL -1 receptor antagonist (rhIL-1RA)] dampened NET-induced changes in IL-8 and TNF-alpha proteins as well as IL-36 alpha RNA. rhIL-36RA limited the increase in expression of proinflammatory cytokine RNAs in HBEs exposed to NETs. NETs selectively upregulate an IL-1 family cytokine response in HBEs, which enhances IL-8 production and is limited by rhIL-1RA. The present findings describe a unique mechanism by which NETs may contribute to inflammation in human lung disease in vivo. NET-driven IL-1 signaling may represent a novel target for modulating inflammation in diseases characterized by a substantial NET burden.