IntroductionThe pathological course of several chronic inflammatory diseases, including cystic fibrosis, chronic obstructive pulmonary disease, and rheumatoid arthritis, features an aberrant innate immune response dominated by neutrophils. In cystic fibrosis, neutrophil burden and activity of neutrophil elastase in the extracellular fluid have been identified as strong predictors of lung disease severity.ReviewAlthough neutrophils are generally considered to be rigid, pre-programmed effector leukocytes, recent studies suggest extensive plasticity in how neutrophil functions unfold upon recruitment to peripheral tissues, and how they choose their ultimate fate. Indeed, upon migration to cystic fibrosis airways, neutrophils display dysregulated lifespan, metabolic activation, and altered effector and regulatory functions, consistent with profound adaptation and phenotypic reprogramming. Licensed by signals present in cystic fibrosis airway microenvironment to survive and develop these novel functions, neutrophils orchestrate, in partnership with the epithelium and with the resident microbiota, the evolution of a pathological microenvironment. This microenvironment is defined by altered proteolytic, redox, and metabolic balance and the presence of stable luminal structures in which neutrophils and microbes coexist.ConclusionsThe elucidation of molecular mechanisms driving neutrophil plasticity in vivo will open new treatment opportunities designed to modulate, rather than block, the crucial adaptive functions fulfilled by neutrophils. This review aims to outline emerging mechanisms of neutrophil plasticity and their participation in the building of pathological microenvironments in the context of cystic fibrosis and other diseases with similar features.

中文翻译：

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中性粒细胞可塑性促进病理微环境的发展：对囊性纤维化气道疾病的影响

介绍几种慢性炎症性疾病的病理过程，包括囊性纤维化、慢性阻塞性肺病和类风湿性关节炎，以中性粒细胞为主的异常先天免疫反应为特征。在囊性纤维化中，细胞外液中的中性粒细胞负荷和中性粒细胞弹性蛋白酶的活性已被确定为肺部疾病严重程度的强有力预测因子。 综述尽管中性粒细胞通常被认为是刚性的、预编程的效应白细胞，但最近的研究表明，中性粒细胞的功能具有广泛的可塑性在招募到外周组织时展开，以及它们如何选择最终命运。事实上，在迁移到囊性纤维化气道后，中性粒细胞显示出寿命失调、代谢激活以及效应子和调节功能改变，与深度适应和表型重编程一致。通过囊性纤维化气道微环境中存在的信号许可，中性粒细胞与上皮细胞和常驻微生物群合作，协调病理微环境的进化，以生存和发展这些新功能。这种微环境的定义是蛋白水解、氧化还原和代谢平衡的改变以及中性粒细胞和微生物共存的稳定管腔结构的存在。结论阐明体内驱动中性粒细胞可塑性的分子机制将开辟新的治疗机会，旨在调节而不是阻止，中性粒细胞完成的关键适应功能。