Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity.
Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity.
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缺氧诱导肺上皮细胞产生肾上腺髓质素，刺激ILC2炎症和免疫。
DOI：
10.1084/jem.20211985
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发表时间：
2022-06-06
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影响因子：
--
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中科院分区：
文献类型：
--
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肺上皮中杆状细胞的低氧诱导ILC2反应增强，导致炎症和免疫增强。通过VHL缺失揭示的机制是HIF2α增加驱动肾上腺髓质素的分泌，从而激活ILC2。低氧参与了几种肺部疾病的呼吸道炎症和重塑；然而，低氧肺上皮如何调节变态反应性炎症仍有待充分表征。在这里，我们报告了肺上皮细胞中E3泛素连接酶VHL的条件性缺失导致了2型反应的加剧，并伴随着稳定状态下和炎症或蠕虫感染后第2组固有淋巴样细胞(ILC2s)的选择性增加。阻断低氧诱导因子2α(HIF2α)的表达可显著逆转VHL介导的ILC2激活。肺上皮细胞VHL缺乏可引起多肽激素肾上腺髓质素(Adrenomedullin，ADM)表达增加，我们的研究结果提示，HIF2α调控Adm的表达。ADM在体外和体内均可直接促进ILC2的激活。我们的研究结果表明，VHLHIF2ADM轴介导的低氧反应是通过增加肺上皮细胞α的表达，导致ILC2激活来控制肺2型反应的关键。
Hypoxia in club cells in the lung epithelium induces increased ILC2 responses, leading to enhanced inflammation and immunity. The mechanism, revealed by VHL deletion, is increased HIF2α driving the secretion of adrenomedullin, which activates ILC2. Hypoxia contributes to airway inflammation and remodeling in several lung diseases; however, exactly how hypoxic pulmonary epithelium regulates allergic inflammation remains to be fully characterized. Here, we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial cells resulted in exacerbated type 2 responses accompanied by selective increase of group 2 innate lymphoid cells (ILC2s) at steady state and following inflammation or helminth infection. Ablation of expression of the hypoxia-inducible factor 2α (HIF2α) significantly reversed VHL-mediated ILC2 activation. VHL deficiency in lung epithelial cells caused increased expression of the peptide hormone adrenomedullin (ADM), and our data suggest that HIF2α controls Adm expression. ADM directly promoted ILC2 activation both in vitro and in vivo. Our findings indicate that the hypoxic response mediated by the VHL–HIF2α axis is critical for control of pulmonary type 2 responses by increasing ADM expression in lung epithelia, causing ILC2 activation.
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影响因子：
8
作者：
Gour N;Smole U;Yong HM;Lewkowich IP;Yao N;Singh A;Gabrielson E;Wills-Karp M;Lajoie S
通讯作者：
Lajoie S
DOI：
10.2147/copd.s126400
发表时间：
2017
影响因子：
2.8
作者：
Dres M;Hausfater P;Foissac F;Bernard M;Joly LM;Sebbane M;Philippon AL;Gil-Jardiné C;Schmidt J;Maignan M;Treluyer JM;Roche N
通讯作者：
Roche N
影响因子：
7.7
作者：
Macias, David;Cowburn, Andrew S.;Johnson, Randall S.
通讯作者：
Johnson, Randall S.
DOI：
10.1073/pnas.1003988107
发表时间：
2010-06-22
影响因子：
11.1
作者：
Price, April E.;Liang, Hong-Erh;Locksley, Richard M.
通讯作者：
Locksley, Richard M.
影响因子：
32.4
作者：
Halim, Timotheus Y. F.;Krauss, Ramona H.;Takei, Fumio
通讯作者：
Takei, Fumio