Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.

中文翻译：

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中性粒细胞通过限制 ILC2 功能和单核细胞-树突状细胞抗原呈递来抑制过敏性气道炎症。


中性粒细胞的动员、募集和清除必须受到严格调节，因为过度旺盛的中性粒细胞炎症与包括哮喘在内的慢性疾病的病理有关。以中性粒细胞为治疗目标的努力未能考虑到它们的多效性功能，以及破坏控制中性粒细胞在稳态和炎症过程中周转的基本调节途径的影响。使用过敏性气道疾病的屋尘螨 (HDM) 模型，我们证明中性粒细胞耗竭意外地导致辅助性 T 2 (TH2) 炎症、上皮重塑和气道阻力加剧。从机制上讲，这是由于全身粒细胞集落刺激因子（G-CSF）浓度显着增加，而该浓度通常在外周受到迁移的肺中性粒细胞的负调节。有趣的是，我们发现增加的 G-CSF 通过直接作用于气道 2 型先天淋巴细胞 (ILC2) 来引发细胞因子的产生，从而增强了暴露于 HDM 的动物的过敏致敏作用。此外，全身G-CSF的增加促进了骨髓单核细胞祖细胞群的扩张，从而导致外周单核细胞衍生的树突细胞库增强，从而增强了抗原呈递。通过模拟中性粒细胞耗竭的影响，我们的研究发现了 G-CSF 在调节 ILC2 功能和抗原呈递方面以前未被认识到的作用。更广泛地说，他们强调了中性粒细胞在限制 TH2 过敏性气道炎症中发挥的意想不到的调节作用。