上皮芳烃受体通过抑制 ROS 触发的 NLRP3 炎性小体来防止哮喘中的黏液产生。
Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma.
机构信息
Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
出版信息
Front Immunol. 2021 Nov 15;12:767508. doi: 10.3389/fimmu.2021.767508. eCollection 2021.
BACKGROUND
Despite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations.
OBJECTIVES
We sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma.
METHODS
Cockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated.
RESULTS
Cockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1β), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1β generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs.
CONCLUSIONS
These results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.
背景
尽管人们早就认识到黏液过度产生在哮喘中的重要性，但它的病因仍知之甚少。Muc5ac 是一种分泌型粘蛋白，与肺功能下降和哮喘恶化有关。
目的
我们试图研究控制哮喘中 Muc5ac 表达和过敏性气道炎症的免疫途径。
方法
在人支气管上皮细胞 (HBEC) 和哮喘小鼠模型中，检测了蟑螂过敏原诱导的 Muc5ac 表达和芳烃受体 (AhR) 信号转导激活。通过 AhR 敲低、拮抗剂 CH223191 和 AhR 小鼠，确定 AhR 对 Muc5ac 表达、线粒体 ROS (Mito-ROS) 生成和 NLRP3 炎性体的调节作用。还研究了 NLRP3 炎性体在 Muc5ac 表达和气道炎症中的作用。
结果
蟑螂过敏原诱导 HBEC 和哮喘小鼠模型气道中 Muc5ac 过表达。还观察到 AhR 及其下游基因 CYP1A1 和 CYP1B1 的表达增加。AhR 缺失的小鼠表现出过敏性气道炎症和 MUC5AC 表达增加。此外，蟑螂过敏原诱导上皮 NLRP3 炎性体激活（例如，NLRP3、Caspase-1 和 IL-1β），通过 AhR 敲低或拮抗剂 CH223191 增强。此外，HBEC 中 AhR 的缺失导致 ROS 生成增加，特别是 Mito-ROS，而 ROS 或 Mito-ROS 的抑制随后抑制了炎性体的激活。重要的是，用 NLRP3 特异性抑制剂 MCC950 抑制炎性体减弱了过敏性气道炎症和 Muc5ac 表达。由激活的炎性体产生的 IL-1β 介导蟑螂过敏原诱导的 HBEC 中 Muc5ac 的表达。
结论
这些结果揭示了 AhR-ROS-NLRP3 炎性体在调节 Muc5ac 表达和气道炎症中的一个以前未被识别的功能轴。
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