Oxidation-Dependent Activation of Src Kinase Mediates Epithelial IL-33 Production and Signaling during Acute Airway Allergen Challenge.
Oxidation-Dependent Activation of Src Kinase Mediates Epithelial IL-33 Production and Signaling during Acute Airway Allergen Challenge.
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DOI：
10.4049/jimmunol.2000995
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发表时间：
2021-06-15
期刊：
影响因子：
--
通讯作者：
van der Vliet A
中科院分区：
文献类型：
--
作者：
Dustin CM;Habibovic A;Hristova M;Schiffers C;Morris CR;Lin MJ;Bauer RA;Heppner DE;Daphtary N;Aliyeva M;van der Vliet A
呼吸道上皮形成了抵抗吸入性病原体的第一道防线，并且作为对环境损伤的先天性细胞因子应答的重要来源。这些应答的一个关键介质是IL-1家族细胞因子IL-33，其在急性上皮损伤时作为警报素快速分泌并诱导2型免疫应答。我们最近的工作强调了NADPH氧化酶双氧化酶1（DUOX 1）在急性气道上皮细胞IL-33分泌的各种空气过敏原，与H2 O2的生产和氧化还原依赖性激活Src激酶和表皮生长因子受体（EGFR）信号的重要性。在这里，我们表明，IL-33的分泌在响应急性气道挑战与屋尘螨（HDM）过敏原关键取决于激活Src的DUOX 1依赖性氧化机制。有趣的是，HDM诱导的上皮IL-33分泌被基于siRNA或抗体的方法显著减弱，以阻断IL-33通过其受体IL 1 RL 1（ST 2）的信号传导，表明HDM诱导的IL-33分泌包括涉及ST 2依赖性IL-33信号传导的正前馈机制。此外，通过直接气道给予IL-33激活2型细胞因子应答与ST 2依赖性DUOX 1介导的H2 O2产生激活以及Src和EGFR基于氧化还原的激活相关，并且在Duox 1 −/−和Src+/−小鼠中减弱，表明IL-33诱导的上皮信号传导和随后的气道应答涉及DUOX 1/Src依赖性途径。总的来说，我们的研究结果表明DUOX 1，Src和IL-33信号之间的复杂关系，在激活先天性2型免疫反应过敏原，涉及DUOX 1依赖性上皮Src/EGFR激活初始IL-33分泌和随后的IL-33信号通过ST 2激活。
The respiratory epithelium forms the first line of defense against inhaled pathogens, and acts as an important source of innate cytokine responses to environmental insults. One critical mediator of these responses is the IL-1 family cytokine, IL-33, which is rapidly secreted upon acute epithelial injury as an alarmin and induces type 2 immune responses. Our recent work highlighted the importance of the NADPH oxidase dual oxidase 1 (DUOX1) in acute airway epithelial IL-33 secretion by various airborne allergens, associated with H2O2 production and redox-dependent activation of Src kinases and epidermal growth factor receptor (EGFR) signaling. Here, we show that IL-33 secretion in response to acute airway challenge with house dust mite (HDM) allergen critically depends on the activation of Src by a DUOX1-dependent oxidative mechanism. Intriguingly, HDM-induced epithelial IL-33 secretion was dramatically attenuated by siRNA- or antibody-based approaches to block IL-33 signaling through its receptor IL1RL1(ST2), indicating that HDM-induced IL-33 secretion includes a positive feed-forward mechanism involving ST2-dependent IL-33 signaling. Moreover, activation of type 2 cytokine responses by direct airway IL-33 administration was associated with ST2-dependent activation of DUOX1-mediated H2O2 production and redox-based activation of Src and EGFR, and was attenuated in Duox1−/− and Src+/− mice, indicating that IL-33-induced epithelial signaling and subsequent airway responses involve DUOX1/Src-dependent pathways. Collectively, our findings suggest an intricate relationship between DUOX1, Src and IL-33 signaling in the activation of innate type 2 immune responses to allergens, involving DUOX1-dependent epithelial Src/EGFR activation in initial IL-33 secretion and in subsequent IL-33 signaling through ST2 activation.
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影响因子：
7.8
作者：
Allen JE;Sutherland TE
通讯作者：
Sutherland TE
DOI：
10.1016/j.jaci.2014.11.037
发表时间：
2015-07
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
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Alam R
影响因子：
4.6
作者：
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通讯作者：
Harnett MM
影响因子：
16.6
作者：
Cohen, E. Suzanne u;Scott, Ian C.;Mustelin, Tomas
通讯作者：
Mustelin, Tomas
DOI：
10.1016/j.jaci.2015.10.003
发表时间：
2016-05
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Hristova M;Habibovic A;Veith C;Janssen-Heininger YM;Dixon AE;Geiszt M;van der Vliet A
通讯作者：
van der Vliet A