GM-CSF instigates a dendritic cell-T-cell inflammatory circuit that drives chronic asthma development
GM-CSF instigates a dendritic cell-T-cell inflammatory circuit that drives chronic asthma development
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粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）引发树突状细胞与T细胞之间的炎症循环，进而推动慢性哮喘的发展。
DOI：
10.1016/j.jaci.2020.12.638
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发表时间：
2021-06-03
影响因子：
14.2
通讯作者：
Kopf, Manfred
中科院分区：
文献类型：
--
作者：
Nobs, Samuel Philip;Pohlmeier, Lea;Kopf, Manfred
背景：激素抵抗性哮喘的特征通常是高水平的中性粒细胞和混合的TH 2/TH 17免疫特征。事实上，中性粒细胞是多种呼吸道疾病中慢性肺部炎症的关键驱动因素。它们的数量与疾病的严重程度密切相关，并且它们的存在通常与慢性肺部炎症的恶化有关。目的：什么因素驱动嗜中性粒细胞介导的慢性肺部疾病的发展在很大程度上仍然未知，我们试图研究GM-CSF作为慢性哮喘的潜在调节剂的作用。使用不同的慢性哮喘实验动物模型，结合肺泡巨噬细胞重建的整体GM-CSF受体敲除小鼠以及细胞类型，结果：我们确定GM-CSF信号转导是调节中性粒细胞在肺部聚集的关键因子。我们表明，虽然不需要本质上调节中性粒细胞迁移，GM-CSF控制肺树突状细胞的功能，这反过来又促进T细胞依赖性的招募中性粒细胞的气道。我们证明GM-CSF以内在方式调节肺树突状细胞抗原摄取、转运和T（H）2/T（H）17细胞引发，这反过来又驱动肺粒细胞募集并有助于慢性疾病气道高反应性的发展。我们将GM-CSF确定为慢性肺部炎症的潜在新治疗靶点，描述了驱动慢性肺病的GM-CSF依赖性肺常规树突细胞-T细胞中性粒细胞轴。
Background: Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed TH2/TH17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation.Objective: What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma.Methods: Different experimental animal models of chronic asthma were used in combination with alveolar macrophage- reconstitution of global GM-CSF receptor knockout mice as well as cell-type-specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation.Results: We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell-dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and T(H)2/T(H)17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease.Conclusions: We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF-dependent lung conventional dendritic cell-T-cellneutrophil axis that drives chronic lung disease.