Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model
Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model
复制标题
阻断 NLRP3/Caspase-1 轴可改善甲苯二异氰酸酯诱发的小鼠哮喘模型中的气道中性粒细胞炎症
DOI：
10.1093/toxsci/kfz099
复制
发表时间：
2019-08-01
影响因子：
3.8
通讯作者：
Tao, Ailin
中科院分区：
文献类型：
--
作者：
Chen, Shuyu;Yao, Lihong;Tao, Ailin
多项研究已经解决了Nod样受体蛋白3（NLRP3）/caspase-1/IL-1 β信号在哮喘中的重要作用。然而，NLRP 3/caspase-1在甲苯二异氰酸酯（TDI）诱导的哮喘中的作用仍然不清楚。本研究的目的是探讨NLRP 3/caspase-1轴在TDI诱导的哮喘中的作用。使用如前所述建立的TDI诱导的哮喘小鼠模型，我们给予哮喘小鼠高选择性NLRP 3抑制剂MCC 950以及特异性半胱天冬酶-1抑制剂VX-765和Ac-YVAD-CHO用于治疗目的。测定气道阻力并分析支气管肺泡灌洗液。采用组织学、免疫组化、Western印迹和流式细胞术对肺进行检查。TDI暴露增加了NLRP 3和caspase-1的表达，这与气道高反应性（AHR）增加、嗜酸性粒细胞为主的细胞浸润、明显的杯状细胞化生、广泛的胶原沉积和T（H）2/T（H）17反应增加相关联。VX-765和Ac-YVAD-CHO均有效抑制TDI哮喘小鼠中caspase-1的活化，除了降低T（H）2反应和降低IL-18和IL-1 β水平外，还伴有AHR、气道炎症和气道重塑的显著减弱。MCC950阻断了TDI暴露小鼠中NLRP 3的激活，并下调了caspase-1、IL-1 β和IL-18的蛋白表达。MCC950还能显著减轻AHR、气道炎症、气道重塑，并显著抑制T（H）2/T（H）17反应。这些发现表明，阻断NLRP 3/caspase-1轴可有效防止TDI诱导的哮喘的进展，并可用作哮喘患者的治疗靶点。
Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1 beta signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased T(H)2/T(H)17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased T(H)2 response and lower levels of IL-18 and IL-1 beta. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1 beta, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed T(H)2/T(H)17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.