Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response.
Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response.
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DOI：
10.1136/thoraxjnl-2017-210326
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发表时间：
2018-08
期刊：
影响因子：
10
通讯作者：
Lee YC
中科院分区：
文献类型：
--
作者：
Jeong JS;Lee KB;Kim SR;Kim DI;Park HJ;Lee HK;Kim HJ;Cho SH;Kolliputi N;Kim SH;Lee YC
已知呼吸道真菌暴露与严重过敏性肺炎相关。气道上皮是过敏性炎症的重要控制者。气道上皮中的天然免疫识别受体、核苷酸结合结构域、富含亮氨酸的家族、含pyrin-domain-containing-3（NLRP 3）炎性体和磷酸肌醇3激酶（PI 3 K）-δ参与各种炎症过程。我们研究了NLRP 3炎性体在真菌诱导的过敏性肺炎症中的作用，并检测了NLRP 3炎性体的调节机制，重点是气道上皮中的PI 3 K-δ。我们使用了两个体内模型暴露于烟曲霉菌（Af）和链格孢菌（Aa），以及AF暴露在体外系统诱导。我们还检测了过敏性支气管肺曲霉病（ABPA）患者肺组织中NLRP 3的表达。NLRP 3炎性体的组装/活化在AF暴露小鼠的肺中增加。在AF刺激的鼠和人上皮细胞中观察到NLRP 3炎性小体组装/活化的升高。类似地，ABPA患者中NLRP 3的肺表达增加。重要的是，NLRP 3炎性体衍生的IL-1β的中和减轻了AF诱导的过敏性炎症的病理生理学特征。此外，PI 3 K-δ阻断剂通过调节NLRP 3炎性体，特别是在上皮细胞中，改善了AF诱导的过敏性炎症。PI 3 K-δ的这种调节作用通过调节线粒体活性氧（mtROS）的产生来介导。NLRP 3炎性体还涉及Aa诱导的嗜酸性变应性炎症，其通过PI 3 K-δ阻断而改善。这些发现表明，真菌诱导的气道上皮中NLRP 3炎性小体的组装/活化可能受到PI 3 K-δ的调节，其部分通过调节mtROS的产生来介导。抑制PI 3 K-δ可能具有治疗真菌诱导的严重过敏性肺部炎症的潜力。
Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes. We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium. We used two in vivo models induced by exposure to Aspergillus fumigatus (Af) and Alternaria alternata (Aa), as well as an Af-exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA). Assembly/activation of NLRP3 inflammasome was increased in the lung of Af-exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af-stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1β alleviated pathophysiological features of Af-induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af-induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa-induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade. These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe allergic lung inflammation.
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影响因子：
2.9
作者：
Agarwal, Ritesh;Gupta, Dheeraj
通讯作者：
Gupta, Dheeraj
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
DOI：
10.4049/jimmunol.1102488
发表时间：
2012-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Allen IC;Jania CM;Wilson JE;Tekeppe EM;Hua X;Brickey WJ;Kwan M;Koller BH;Tilley SL;Ting JP
通讯作者：
Ting JP
影响因子：
5.4
作者：
Kim, So Ri;Lee, Kyung Sun;Lee, Yong Chul
通讯作者：
Lee, Yong Chul
DOI：
10.1164/rccm.200805-737oc
发表时间：
2009-01-01
影响因子：
24.7
作者：
Denning, David W.;O'Driscoll, B. Ronan;Niven, Robert M.
通讯作者：
Niven, Robert M.