NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection
NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection
复制标题
NOD 样受体家族，含热蛋白结构域 3 (NLRP3) 有助于鼻病毒感染时人气道上皮的炎症、焦亡和粘蛋白产生
DOI：
10.1016/j.jaci.2019.05.006
复制
发表时间：
2019-09-01
影响因子：
14.2
通讯作者：
Li, Chun Wei
中科院分区：
文献类型：
--
作者：
Liu, Tao;Zhou, Yu Tao;Li, Chun Wei
背景：气道上皮维持粘膜稳态并对病原体做出有效反应。上皮NOD样受体家族、含有pyrin结构域3（NLRP3）炎症小体在人鼻病毒（hRV）感染中的作用及其介导上皮功能变化的作用仍知之甚少。目的：我们研究上皮NLRP3炎症小体介导hRV感染的机制和细胞功能。方法：利用hRV感染的原代人鼻上皮祖细胞和分化的人鼻上皮细胞（hNEC）模型，我们对 NLRP3 炎性体激活、细胞死亡和粘液产生的关键因素进行功能检查。此外，还评估了hRV诱导的鼻粘膜炎症中人上皮中的NLRP3和IL-1β。结果：hRV感染后人鼻上皮祖细胞和hNEC中炎症小体介导的IL-1β分泌和细胞焦亡依赖于DDX33/DDX58-NLRP3-caspase-1-GSDMD轴。在分化的 hNEC 中，hRV 还可以通过该轴促进主要气道上皮粘蛋白（MUC5AC）的产生。我们的结果进一步证实NLRP3炎症小体信号通路负责抑制气道上皮中的hRV复制。最后，慢性炎症鼻粘膜中的hRV感染与上皮粘液过度产生相关，而与无病毒感染的正常上皮相比，在杯状细胞增生的hRV感染上皮中，NLRP3和IL-1β表达水平显着增加。 结论：目前的研究表明，NLRP3炎症小体信号轴可以功能性介导hRV诱导的气道上皮炎症、细胞焦亡和粘液产生，这可能是与 hRV 诱导的气道重塑相关的重要机制。
Background: The airway epithelium maintains mucosal homeostasis and effectively responds to pathogens. The roles of the epithelial NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in human rhinovirus (hRV) infection and its effects mediating epithelial functional changes remain poorly understood.Objective: We investigated the mechanisms and cellular functions mediated by the epithelial NLRP3 inflammasome on hRV infection.Methods: Using models of primary human nasal epithelial progenitor cells and differentiated human nasal epithelial cells (hNECs) infected by hRV, we functionally examined key factors for NLRP3 inflammasome activation, cell death, and mucus production. Furthermore, NLRP3 and IL-1 beta in human epithelium from nasal mucosal inflammation induced by hRV were evaluated.Results: The inflammasome-mediated IL-1 beta secretion and pyroptosis in human nasal epithelial progenitor cells and hNECs on hRV infection were dependent on the DDX33/DDX58-NLRP3-caspase-1-GSDMD axis. In differentiated hNECs hRV could also promote major airway epithelial mucin (MUC5AC) production through this axis. Our results further confirmed that the NLRP3 inflammasome signaling pathway was responsible for suppressing hRV replication in airway epithelium. Finally, hRV infection in chronically inflamed nasal mucosa was associated with epithelial mucus hyperproduction, whereas NLRP3 and IL-1 beta expression levels were significantly increased in hRV-infected epithelium with goblet cell hyperplasia compared with normal epithelium without viral infection.Conclusion: The current study showed that the NLRP3 inflammasome signaling axis could functionally mediate hRV-induced inflammation, pyroptosis, and mucus production in airway epithelium, which might be an essential mechanism associated with hRV-induced airway remodeling.