Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

中文翻译：

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TLR配体介导的但不是蛋白酶介导的过敏性气道炎症需要TNF。

哮喘与接触多种过敏原和佐剂有关。人们对由这些多种药物触发的细胞机制和分子机制之间存在重叠的程度了解甚少，但这可能解释了患者对特定疗法的不同反应。特别是，尚不清楚为什么部分（而非全部）患者受益于TNF的阻断。在这里，我们表征了过敏敏化过程中由不同类型的佐剂触发的信号通路。使用TLR配体或屋尘提取物作为佐剂对无害蛋白质敏感的小鼠在变应原激发后会产生嗜酸性和嗜中性的气道炎症混合以及气道高反应性（AHR），而使用蛋白酶作为佐剂致敏的小鼠则主要发生嗜酸性和AHR。在过敏性致敏过程中，TLR配体而非蛋白酶诱导了TNF。TNF通过气道上皮细胞发出信号，以重新编程并促进Th2（而非Th17）在淋巴结中的发育。在中性粒细胞和嗜酸性粒细胞炎症的变应原激发阶段也需要TNF。相反，在蛋白酶介导的哮喘模型中，TNF对于过敏性气道疾病是必不可少的。这些发现可能有助于解释为什么TNF阻断只能改善部分哮喘患者的肺功能。在蛋白酶介导的哮喘模型中，TNF可用于过敏性气道疾病。这些发现可能有助于解释为什么TNF阻断只能改善部分哮喘患者的肺功能。在蛋白酶介导的哮喘模型中，TNF可用于过敏性气道疾病。这些发现可能有助于解释为什么TNF阻断只能改善部分哮喘患者的肺功能。