CaMKII oxidation regulates cockroach allergen-induced mitophagy in asthma.
CaMKII oxidation regulates cockroach allergen-induced mitophagy in asthma.
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DOI：
10.1016/j.jaci.2020.08.033
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Gao P
中科院分区：
文献类型：
--
作者：
Zhang Y;Do DC;Hu X;Wang J;Zhao Y;Mishra S;Zhang X;Wan M;Gao P
自噬在环境污染物和呼吸道感染引起的炎症反应中起重要作用。我们试图研究蟑螂变应原诱导的过度激活的自噬在过敏性气道炎症中的作用及其潜在的分子机制。本研究观察了环境变应原诱导的原代人支气管上皮细胞（HBECs）和哮喘小鼠模型及患者肺组织的自噬作用。在哮喘小鼠模型中，使用自噬抑制剂3-甲基腺嘌呤检测自噬在哮喘发生中的作用。此外，在过敏原处理的HBEC和小鼠模型中，检测了活性氧（ROS）和氧化型Ca 2 +/钙调素依赖性蛋白激酶II（ox-CaMKII）信号在调节哮喘期间自噬中的参与。蟑螂变应原激活哮喘患者和小鼠HBEC和肺组织中的自噬。自噬抑制剂3-甲基腺嘌呤显著减弱气道高反应性、TH 2相关的肺部炎症和ROS生成。从机制上讲，我们证明了蟑螂过敏原诱导的ROS和自噬之间的病理前馈电路是通过CaMKII氧化介导的。此外，具有ROS抗性CaMKII MM-VVδ的转基因小鼠显示出TH 2相关的肺部炎症和自噬的减弱。腺病毒介导的线粒体ox-CaMKII抑制作用抑制了蟑螂变应原诱导的HBEC自噬、线粒体功能障碍、线粒体自噬和细胞因子的产生最后，线粒体CaMKII抑制的表达的一个关键的泛素结合的自噬受体，视神经磷酸酶，其招聘到破碎的线粒体。视神经磷酸酶敲低抑制蟑螂过敏诱导的线粒体自噬。我们的数据表明，过敏原-ROS-ox-CaMKII-线粒体自噬在过敏性气道炎症和哮喘的发展中的一个先前发现的轴。
Autophagy plays an important role in causing inflammatory responses initiated by environmental pollutants and respiratory tract infection. We sought to investigate the role of cockroach allergen–induced excessive activation of autophagy in allergic airway inflammation and its underlying molecular mechanisms. Environmental allergen–induced autophagy was investigated in the primary human bronchial epithelial cells (HBECs) and lung tissues of asthmatic mouse model and patients. The role of autophagy in asthma development was examined by using autophagy inhibitor 3-methyladenine in an asthma mouse model. Furthermore, the involvements of reactive oxygen species (ROS) and oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) signaling in regulating autophagy during asthma were examined in allergen-treated HBECs and mouse model. Cockroach allergen activated autophagy in HBECs and in the lung tissues from asthmatic patients and mice. Autophagy inhibitor 3-methyladenine significantly attenuated airway hyperresponsiveness, TH2-associated lung inflammation, and ROS generation. Mechanistically, we demonstrated a pathological feedforward circuit between cockroach allergen–induced ROS and autophagy that is mediated through CaMKII oxidation. Furthermore, transgenic mice with ROS-resistant CaMKII MM-VVδ showed attenuation of TH2-associated lung inflammation and autophagy. Mitochondrial ox-CaMKII inhibition induced by adenovirus carrying mitochondrial-targeted inhibitor peptide CaMKIIN suppresses cockroach allergen–induced autophagy, mitochondrial dysfunction, mitophagy, and cytokine production in HBECs. Finally, mitochondrial CaMKII inhibition suppressed the expression of one of the key ubiquitin-binding autophagy receptors, optineurin, and its recruitment to fragmented mitochondria. Optineurin knockdown inhibited cockroach allergy–induced mitophagy. Our data suggest a previously uncovered axis of allergen-ROS-ox-CaMKII-mitophagy in the development of allergic airway inflammation and asthma.
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影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.1402277
发表时间：
2015-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abdel Fattah E;Bhattacharya A;Herron A;Safdar Z;Eissa NT
通讯作者：
Eissa NT
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：
5
作者：
Luczak, Elizabeth D.;Anderson, Mark E.
通讯作者：
Anderson, Mark E.
影响因子：
11.5
作者：
Jang, Ji Eun;Eom, Ju-In;Min, Yoo Hong
通讯作者：
Min, Yoo Hong