Neutrophil Extracellular Traps Augmented Alveolar Macrophage Pyroptosis via AIM2 Inflammasome Activation in LPS-Induced ALI/ARDS.
Neutrophil Extracellular Traps Augmented Alveolar Macrophage Pyroptosis via AIM2 Inflammasome Activation in LPS-Induced ALI/ARDS.
复制标题
LPS 诱导的 ALI/ARDS 中中性粒细胞胞外陷阱通过 AIM2 炎症小体激活增强肺泡巨噬细胞焦亡
DOI：
10.2147/jir.s321513
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发表时间：
2021
影响因子：
4.5
通讯作者：
Pan P
中科院分区：
文献类型：
--
作者：
Li H;Li Y;Song C;Hu Y;Dai M;Liu B;Pan P
背景：不可控的炎症是革兰阴性菌肺炎引起的急性呼吸窘迫综合征（ARDS）的一个重要特征。中性粒细胞和肺泡巨噬细胞都参与炎症，但它们的相互作用如何增强炎症并触发ARDS尚不清楚。作者推测，中性粒细胞胞外陷阱（NETs），这是形成于中性粒细胞NETosis，部分原因肺泡巨噬细胞焦亡和恶化的严重程度ARDS。方法首先分析NETs和caspase-1在ARDS临床病例中的表达情况。然后，作者采用脂多糖（LPS）诱导的ARDS模型来研究靶向NET或肺泡巨噬细胞是否具有保护作用。AIM 2传感器可以与DNA结合以促进AIM 2炎性小体激活，因此作者研究了NET DNA降解或AIM 2基因沉默是否可以保护肺泡巨噬细胞免受体外焦亡。结果急性呼吸窘迫综合征（ARDS）患者肺组织上清液中NET和caspase-1的水平与ARDS的严重程度相关，死亡组NET和caspase-1的水平高于存活组。在体内，LPS攻击小鼠伤后24 h支气管肺泡灌洗液（BALF）中NET水平和炎性肺泡巨噬细胞比例明显高于对照组。给予DNase I（NET DNA降解剂）和BB-Cl-脒（NET形成抑制剂）可减轻肺泡巨噬细胞的焦亡，Ac-YVAD-cmk（焦亡抑制剂）可减少BALF中的NET水平和肺泡中的中性粒细胞浸润。所有治疗均明显减轻了ARDS的严重程度。值得注意的是，脂多糖导致NET诱导肺泡巨噬细胞火灾，NET DNA降解或AIM 2基因沉默可防止肺泡巨噬细胞火灾。结论NETs介导肺泡巨噬细胞与嗜中性粒细胞的相互作用，从而影响ARDS的发生发展。
Background Uncontrollable inflammation is a critical feature of gram-negative bacterial pneumonia-induced acute respiratory distress syndrome (ARDS). Both neutrophils and alveolar macrophages participate in inflammation, but how their interaction augments inflammation and triggers ARDS is unclear. The authors hypothesize that neutrophil extracellular traps (NETs), which are formed during neutrophil NETosis, partly cause alveolar macrophage pyroptosis and worsen the severity of ARDS. Methods The authors first analysed whether NETs and caspase-1 are involved in clinical cases of ARDS. Then, the authors employed a lipopolysaccharide (LPS)-induced ARDS model to investigate whether targeting NETs or alveolar macrophages is protective. The AIM2 sensor can bind to DNA to promote AIM2 inflammasome activation, so the authors studied whether degradation of NET DNA or silencing of the AIM2 gene could protect alveolar macrophages from pyroptosis in vitro. Results Analysis of aspirate supernatants from ARDS patients showed that NET and caspase-1 levels were correlated with the severity of ARDS and that the levels of NETs and caspase-1 were higher in nonsurvivors than in survivors. In vivo, the NET level and proportion of pyroptotic alveolar macrophages in bronchoalveolar lavage fluid (BALF) were obviously higher in LPS-challenged mice than in control mice 24 h after injury. Administration of DNase I (a NET DNA-degrading agent) and BB-Cl-amidine (a NET formation inhibitor) alleviated alveolar macrophage pyroptosis, and Ac-YVAD-cmk (a pyroptosis inhibitor) attenuated NET levels in BALF and neutrophil infiltration in alveoli. All treatments markedly attenuated the severity of ARDS. Notably, LPS causes NETs to induce alveolar macrophage pyroptosis, and degradation of NET DNA or silencing of the AIM2 gene protected against alveolar macrophage pyroptosis. Conclusion These findings shed light on the proinflammatory role of NETs in mediating the neutrophil–alveolar macrophage interaction, which influences the progression of ARDS.