肥大细胞移位浸润气道上皮通过IL-33调节哮喘炎症
2019/09/09
摘要
哮喘是一种异质性综合征，已细分为生理表型和分子内型。哮喘最特异的生理表型是间接气道高反应性（AHR），最显著的分子内型是2型炎症。2型炎症的内在机制及其与AHR的关系尚不完全清楚。我们评估了2型细胞因子在有或无哮喘的受试者气道中的表达，这些受试者具有广泛的AHR特征。通过对气道壁的定量形态测量，我们发现肥大细胞从粘膜下层转移到气道上皮，与2型炎症和间接气道高反应特异性相关。利用与肥大细胞共培养的原发性气道上皮细胞体外模型，我们发现，肥大细胞中的上皮源性白细胞介素33独特地诱导了2型细胞因子，从而在前馈环中调节了上皮性白细胞介素33的表达。这种前馈回路在哮喘患者的上皮细胞中更为突出。这些结果表明，哮喘患者的2型炎症和间接AHR与肥大细胞转移浸润气道上皮细胞有关，肥大细胞通过IL-33与上皮细胞协同调节2型炎症。
Airway epithelium-shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling.
Altman MC, Lai Y, Nolin JD, Long S, Chen CC, Piliponsky AM, Altemeier WA, Larmore M, Frevert CW, Mulligan MS, Ziegler SF, Debley JS, Peters MC, Hallstrand TS.
Abstract
Asthma is a heterogeneous syndrome that has been subdivided into physiological phenotypes and molecular endotypes. The most specific phenotypic manifestation of asthma is indirect airway hyperresponsiveness (AHR), and a prominent molecular endotype is the presence of type-2 inflammation. The underlying basis for type-2 inflammation and its relationship to AHR are incompletely understood. We assessed the expression of type-2 cytokines in the airways of subjects with and without asthma who were extensively characterized for AHR. Using quantitative morphometry of the airway wall, we identified a shift in mast cells from the submucosa to the airway epithelium specifically associated with both type-2 inflammation and indirect AHR. Using ex vivo modeling of primary airway epithelial cells in organotypic co-culture with mast cells, we have shown that epithelial-derived IL-33 uniquely induced type-2 cytokines in mast cells, which regulated the expression of epithelial IL33 in a feedforward loop. This feedforward loop was accentuated in epithelial cells derived from subjects with asthma. These results demonstrate that type-2 inflammation and indirect AHR in asthma are related to a shift in mast cell infiltration to the airway epithelium, and that mast cells cooperate with epithelial cells through IL-33 signaling to regulate type-2 inflammation.
哮喘是一种异质性综合征，已细分为生理表型和分子内型。哮喘最特异的生理表型是间接气道高反应性（AHR），最显著的分子内型是2型炎症。2型炎症的内在机制及其与AHR的关系尚不完全清楚。我们评估了2型细胞因子在有或无哮喘的受试者气道中的表达，这些受试者具有广泛的AHR特征。通过对气道壁的定量形态测量，我们发现肥大细胞从粘膜下层转移到气道上皮，与2型炎症和间接气道高反应特异性相关。利用与肥大细胞共培养的原发性气道上皮细胞体外模型，我们发现，肥大细胞中的上皮源性白细胞介素33独特地诱导了2型细胞因子，从而在前馈环中调节了上皮性白细胞介素33的表达。这种前馈回路在哮喘患者的上皮细胞中更为突出。这些结果表明，哮喘患者的2型炎症和间接AHR与肥大细胞转移浸润气道上皮细胞有关，肥大细胞通过IL-33与上皮细胞协同调节2型炎症。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Clin Invest. 2019 Aug 22. pii: 126402. doi: 10.1172/JCI126402.)
(J Clin Invest. 2019 Aug 22. pii: 126402. doi: 10.1172/JCI126402.)
Airway epithelium-shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling.
Altman MC, Lai Y, Nolin JD, Long S, Chen CC, Piliponsky AM, Altemeier WA, Larmore M, Frevert CW, Mulligan MS, Ziegler SF, Debley JS, Peters MC, Hallstrand TS.
Abstract
Asthma is a heterogeneous syndrome that has been subdivided into physiological phenotypes and molecular endotypes. The most specific phenotypic manifestation of asthma is indirect airway hyperresponsiveness (AHR), and a prominent molecular endotype is the presence of type-2 inflammation. The underlying basis for type-2 inflammation and its relationship to AHR are incompletely understood. We assessed the expression of type-2 cytokines in the airways of subjects with and without asthma who were extensively characterized for AHR. Using quantitative morphometry of the airway wall, we identified a shift in mast cells from the submucosa to the airway epithelium specifically associated with both type-2 inflammation and indirect AHR. Using ex vivo modeling of primary airway epithelial cells in organotypic co-culture with mast cells, we have shown that epithelial-derived IL-33 uniquely induced type-2 cytokines in mast cells, which regulated the expression of epithelial IL33 in a feedforward loop. This feedforward loop was accentuated in epithelial cells derived from subjects with asthma. These results demonstrate that type-2 inflammation and indirect AHR in asthma are related to a shift in mast cell infiltration to the airway epithelium, and that mast cells cooperate with epithelial cells through IL-33 signaling to regulate type-2 inflammation.
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高中性粒细胞哮喘患者血清IgE、OCS依赖性和IL-17／22表达水平升高
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转胶蛋白-2在癌症和哮喘中的生化和临床意义
