Bronchial epithelial pyroptosis promotes airway inflammation in a murine model of toluene diisocyanate-induced asthma.
Bronchial epithelial pyroptosis promotes airway inflammation in a murine model of toluene diisocyanate-induced asthma.
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DOI：
10.1016/j.biopha.2020.109925
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发表时间：
2020-01
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影响因子：
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通讯作者：
J. Zhuang;H. Cui;Lili Zhuang;Z. Zhai;Fangyuan Yang;Guihu Luo;Juan He;Hai-Jin Zhao;Wenqu Zhao;Yi He;E. Sun
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文献类型：
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作者：
J. Zhuang;H. Cui;Lili Zhuang;Z. Zhai;Fangyuan Yang;Guihu Luo;Juan He;Hai-Jin Zhao;Wenqu Zhao;Yi He;E. Sun
甲苯二异氰酸酯(TDI)等过敏原对呼吸道上皮细胞的损伤可导致持续的呼吸道炎症。上睑下垂被认为是一种强烈的促炎细胞死亡过程。然而，在TDI诱导的哮喘中，嗜热性下垂在支气管上皮损伤和呼吸道炎症中的作用尚不清楚。然后建立了TDI诱导的实验性哮喘小鼠模型进行活体研究，发现TDI可诱导16HBE细胞发生下垂，表现为Caspase-1表达增强，乳酸脱氢酶、IL-1β和HMGB1水平升高。正如预期的那样，一种特定的NLRP3炎性小体抑制剂显著阻止了TDI诱导的炎性细胞死亡。有趣的是，在哮喘小鼠中，NLRP3炎症体抑制剂降低了caspase-1和焦链执行因子Gasdermin D(GSDMD)在支气管上皮细胞中的裂解增加。此外，抑制NLRP3炎性小体可减轻气道高反应性和气道炎症，并伴随IL-1IgE和Th2型相关细胞因子水平的降低。我们的数据表明，支气管上皮性炎性下垂通过激活NLRP3炎性小体和GSDND裂解加重了TDI型哮喘的气道炎症和高反应性。因此，NLRP3炎性小体介导的上睑下垂可能成为治疗TDI诱导哮喘的潜在靶点。
Airway epithelial injury in response to allergens such as toluene diisocyanate (TDI) leads to persistent airway inflammation. Pyroptosis is recognized as a strong proinflammatory cell death process. However, the role of pyroptosis in bronchial epithelial injury and airway inflammation in TDI-induced asthma remains unknown.In this study, cytotoxic effect of TDI on 16HBE cells (a human bronchial epithelial cell line) was detected. Then a TDI-induced experimental asthma mouse model was established forin vivostudy.Here we found that TDI induced pyroptosis in 16HBE cells, as evidenced by enhanced expressions of caspase-1 and elevated levels of LDH, IL-1β and HMGB1. As expected, TDI-induced inflammatory cell death was significantly blocked by a specific NLRP3 inflammasome inhibitor. Intriguingly, in asthmatic mice, the increased cleavages of caspase-1 and pyroptotic executioner gasdermin D (GSDMD) in bronchial epithelial cells were decreased by NLRP3 inflammasome inhibitor. Furthermore, inhibition of NLRP3 inflammasome attenuated airway hyper-responsiveness and airway inflammation, accompanied by lower levels of IL-1β, IgE and Th2-related cytokines.Our data suggest that bronchial epithelial pyroptosis exacerbates airway inflammation and hyper-responsiveness in TDI-induced asthma via NLRP3 inflammasome activation and GSDND cleavage. Therefore, NLRP3 inflammasome-mediated pyroptosis may be a potential treatment target for TDI-induced asthma.