Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9 -expressing pathogenic T H 2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C ) and CCR2 -expressing monocyte-derived cells (MCs) were uniquely enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a T H 2–mononuclear phagocyte–basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Our findings therefore suggest that pathogenic effector circuits and the absence of proresolution programs drive structural airway disease in response to type 2 inflammation.

中文翻译：

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哮喘恶化的人类模型揭示了过敏性哮喘特有的转录程序和细胞回路


哮喘是一种慢性疾病，最常与过敏和 2 型炎症相关。然而，将气道炎症与哮喘的结构变化联系起来的机制尚不完全清楚。使用过敏原诱发的哮喘恶化的人类模型，我们使用单细胞 RNA 测序比较了过敏性哮喘患者和过敏性非哮喘对照的下气道粘膜。为了应对过敏原，哮喘气道上皮是高度动态的，并且上调的基因涉及基质降解、粘液化生和糖酵解，但未能诱导对照组观察到的损伤修复和抗氧化途径。白细胞介素9 -表达致病性T H 2 细胞对哮喘气道具有特异性，仅在过敏原激发后才能观察到。此外，传统的 2 型树突状细胞（DC2 表达CD1C ） 和CCR2表达单核细胞来源的细胞 (MC) 在过敏原后的哮喘患者中独特富集，并上调维持 2 型炎症并促进病理性气道重塑的基因。相比之下，过敏对照中巨噬细胞样 MC 的含量丰富，在过敏原攻击后上调组织修复程序，表明这些群体可以预防哮喘气道重塑。细胞相互作用分析揭示了 T H 2-单核吞噬细胞-基底细胞相互作用组是哮喘患者特有的。 这些致病细胞回路的特征是免疫和结构细胞的 2 型编程以及可能维持和放大 2 型信号的其他途径，包括 TNF 家族信号传导、细胞代谢改变、抗氧化反应失败以及生长因子信号传导丧失。因此，我们的研究结果表明，致病效应电路和促消退程序的缺乏会导致结构性气道疾病响应 2 型炎症。