内皮细胞与过敏原先天反应和变应性哮喘发生
2018/11/14
摘要
蛋白酶激活受体2（PAR-2）是一种气道上皮模式识别受体（PRR），参与屋尘螨诱导（HDM诱导）哮喘的发生。本研究中，我们猜想高PAR-2表达的肺内皮细胞和促血管生成造血祖细胞（PACs）促进变应性哮喘的发生。HDM提取物（HDME）蛋白酶过敏原在气道粘膜深处被发现，它破坏了内皮屏障。肺内皮细胞和PAC受HDME刺激释放Th2促进细胞因子IL-1α和GM-CSF，并且内皮细胞具有PAC衍生的VEGF-C依赖性血管出芽。通过抑制VEGF-C信号传导阻断血管生成反应减少了HDM模型中炎症和气道重塑的发展。用PAR-2缺陷的骨髓重建WT小鼠的骨髓也减少了气道炎症和重塑。已经暴露于HDME的PAC的过继转移诱导血管生成和Th2炎症，其重塑类似于过敏原攻击诱导的重塑。我们的研究结果确定气道中的肺内皮和PAC可感知过敏原并引发血管生成反应，这是Th2炎症固有的非免疫起源的核心。
Endothelial cells in the innate response to allergens and initiation of atopic asthma.
Kewal Asosingh, Kelly Weiss, Kimberly Queisser, Nicholas Wanner, Mei Yin, Mark Aronica, and Serpil Erzurum.
Abstract
Protease-activated receptor 2 (PAR-2), an airway epithelial pattern recognition receptor (PRR), participates in the genesis of house dust mite-induced (HDM-induced) asthma. Here, we hypothesized that lung endothelial cells and proangiogenic hematopoietic progenitor cells (PACs) that express high levels of PAR-2 contribute to the initiation of atopic asthma. HDM extract (HDME) protease allergens were found deep in the airway mucosa and breaching the endothelial barrier. Lung endothelial cells and PACs released the Th2-promoting cytokines IL-1α and GM-CSF in response to HDME, and the endothelium had PAC-derived VEGF-C-dependent blood vessel sprouting. Blockade of the angiogenic response by inhibition of VEGF-C signaling lessened the development of inflammation and airway remodeling in the HDM model. Reconstitution of the bone marrow in WT mice with PAR-2-deficient bone marrow also reduced airway inflammation and remodeling. Adoptive transfer of PACs that had been exposed to HDME induced angiogenesis and Th2 inflammation with remodeling similar to that induced by allergen challenge. Our findings identify that lung endothelium and PACs in the airway sense allergen and elicit an angiogenic response that is central to the innate nonimmune origins of Th2 inflammation.
蛋白酶激活受体2（PAR-2）是一种气道上皮模式识别受体（PRR），参与屋尘螨诱导（HDM诱导）哮喘的发生。本研究中，我们猜想高PAR-2表达的肺内皮细胞和促血管生成造血祖细胞（PACs）促进变应性哮喘的发生。HDM提取物（HDME）蛋白酶过敏原在气道粘膜深处被发现，它破坏了内皮屏障。肺内皮细胞和PAC受HDME刺激释放Th2促进细胞因子IL-1α和GM-CSF，并且内皮细胞具有PAC衍生的VEGF-C依赖性血管出芽。通过抑制VEGF-C信号传导阻断血管生成反应减少了HDM模型中炎症和气道重塑的发展。用PAR-2缺陷的骨髓重建WT小鼠的骨髓也减少了气道炎症和重塑。已经暴露于HDME的PAC的过继转移诱导血管生成和Th2炎症，其重塑类似于过敏原攻击诱导的重塑。我们的研究结果确定气道中的肺内皮和PAC可感知过敏原并引发血管生成反应，这是Th2炎症固有的非免疫起源的核心。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Clin Invest. 2018 Jul 2; 128(7): 3116–3128.)
(J Clin Invest. 2018 Jul 2; 128(7): 3116–3128.)
Endothelial cells in the innate response to allergens and initiation of atopic asthma.
Kewal Asosingh, Kelly Weiss, Kimberly Queisser, Nicholas Wanner, Mei Yin, Mark Aronica, and Serpil Erzurum.
Abstract
Protease-activated receptor 2 (PAR-2), an airway epithelial pattern recognition receptor (PRR), participates in the genesis of house dust mite-induced (HDM-induced) asthma. Here, we hypothesized that lung endothelial cells and proangiogenic hematopoietic progenitor cells (PACs) that express high levels of PAR-2 contribute to the initiation of atopic asthma. HDM extract (HDME) protease allergens were found deep in the airway mucosa and breaching the endothelial barrier. Lung endothelial cells and PACs released the Th2-promoting cytokines IL-1α and GM-CSF in response to HDME, and the endothelium had PAC-derived VEGF-C-dependent blood vessel sprouting. Blockade of the angiogenic response by inhibition of VEGF-C signaling lessened the development of inflammation and airway remodeling in the HDM model. Reconstitution of the bone marrow in WT mice with PAR-2-deficient bone marrow also reduced airway inflammation and remodeling. Adoptive transfer of PACs that had been exposed to HDME induced angiogenesis and Th2 inflammation with remodeling similar to that induced by allergen challenge. Our findings identify that lung endothelium and PACs in the airway sense allergen and elicit an angiogenic response that is central to the innate nonimmune origins of Th2 inflammation.
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高T2型及低T2型哮喘气道免疫功能紊乱的转录组测定
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英国生物样本库的全基因组跨性状分析突出强调了哮喘和过敏性疾病的共同遗传结构
