Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma.
Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma.
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上皮芳基碳氢化合物受体通过抑制哮喘中 ROS 触发的 NLRP3 炎症小体来防止粘液产生
DOI：
10.3389/fimmu.2021.767508
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发表时间：
2021
影响因子：
7.3
通讯作者：
Gao P
中科院分区：
文献类型：
--
作者：
Hu X;Shen Y;Zhao Y;Wang J;Zhang X;Tu W;Kaufman W;Feng J;Gao P
背景：尽管长期以来人们已经认识到粘液过度产生在哮喘中的重要性，但对其病因仍知之甚少。MUC5AC是一种分泌型粘蛋白，与肺功能降低和哮喘加重有关。目的探讨哮喘时控制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(HBECs)和小鼠哮喘模型上检测蟑螂变应原诱导的Muc5ac表达和芳香烃受体(AhR)信号的激活。AHR通过AhR基因敲除、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炎症体的调节。研究NLRP3炎性小体在Muc5ac表达和气道炎症中的作用。结果蟑螂变应原诱导哮喘小鼠HBECs和呼吸道Muc5ac过度表达。AhR及其下游基因CYP1A1和CYP1B1的表达也增加。AhR缺失的小鼠表现出过敏性气道炎症和MUC5AC表达增加。此外，蟑螂变应原诱导上皮性NLRP3炎症体激活(如NLRP3、Caspase-1和IL-1β)，该激活可被AhR基因敲除或拮抗剂CH223191增强。此外，HBEC中AhR的缺失导致ROS的产生增加，尤其是Mito-ROS，抑制ROS或Mito-Ros随后抑制炎症体的激活。重要的是，用NLRP3特异性抑制剂MCC950抑制炎症小体，可以减轻过敏性呼吸道炎症和Muc5ac的表达。激活的炎性小体产生的IL-1β介导蟑螂变应原诱导HBEC表达Muc5ac。结论这些结果揭示了AhR-ROS-NLRP3炎性小体在调节Muc5ac表达和呼吸道炎症中的功能轴。
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.
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DOI：
10.1016/j.jaci.2018.08.023
发表时间：
2019-04
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Ke X;Do DC;Li C;Zhao Y;Kollarik M;Fu Q;Wan M;Gao P
通讯作者：
Gao P
影响因子：
4
作者：
Kennedy CR;Goya Grocin A;Kovačič T;Singh R;Ward JA;Shenoy AR;Tate EW
通讯作者：
Tate EW
影响因子：
29
作者：
Hooftman, Alexander;Angiari, Stefano;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
DOI：
10.1016/j.jaci.2021.02.040
发表时间：
2021-11
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Altman MC;Calatroni A;Ramratnam S;Jackson DJ;Presnell S;Rosasco MG;Gergen PJ;Bacharier LB;O'Connor GT;Sandel MT;Kattan M;Wood RA;Visness CM;Gern JE;Inner City Asthma Consortium
通讯作者：
Inner City Asthma Consortium
影响因子：
8
作者：
Jia, Zhirong;Bao, Kaifan;Hong, Min
通讯作者：
Hong, Min