Tirouvanziam Rabindra, Gernez Yael, Conrad Carol K, Moss Richard B, Schrijver Iris, Dunn Colleen E, Davies Zoe A, Herzenberg Leonore A, Herzenberg Leonard A
Departments of Pediatrics, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4335-9. doi: 10.1073/pnas.0712386105. Epub 2008 Mar 11.
Blood neutrophils recruited to cystic fibrosis (CF) airways are believed to be rapidly killed by resident bacteria and to passively release elastase and other toxic by-products that promote disease progression. By single-cell analysis, we demonstrate that profound functional and signaling changes readily occur within viable neutrophils recruited to CF airways, compared with their blood counterparts. Airway neutrophils have undergone conventional activation, as shown by decreased intracellular glutathione, increased lipid raft assembly, surface mobilization of CD11b+ and CD66b+ granules, and increased levels of the cytoskeleton-associated phospho-Syk kinase. Unexpectedly, they also mobilize to the surface CD63+ elastase-rich granules, usually confined intracellularly, and lose surface expression of CD16 and CD14, both key receptors in phagocytosis. Furthermore, they express CD80, major histocompatibility complex type II, and the prostaglandin D2 receptor CD294, all normally associated with other lineages, which reflects functional reprogramming. This notion is reinforced by their decreased total phosphotyrosine levels, mirroring a postactivated stage, and increased levels of the phospho-S6 ribosomal protein, a key anabolic switch. Thus, we identified a subset of neutrophils within CF airways with a viable but dysfunctional phenotype. This subset provides a possible therapeutic target and indicates a need to revisit current paradigms of CF airway disease.
招募到囊性纤维化（CF）气道的血液中性粒细胞被认为会迅速被常驻细菌杀死，并被动释放弹性蛋白酶和其他促进疾病进展的有毒副产物。通过单细胞分析，我们证明，与血液中的中性粒细胞相比，招募到CF气道的存活中性粒细胞内很容易发生深刻的功能和信号变化。气道中性粒细胞已经经历了传统激活，表现为细胞内谷胱甘肽减少、脂筏组装增加、CD11b+和CD66b+颗粒的表面动员以及细胞骨架相关磷酸化Syk激酶水平升高。出乎意料的是，它们还会将通常局限于细胞内的富含弹性蛋白酶的CD63+颗粒动员到表面，并失去吞噬作用中的两个关键受体CD16和CD14的表面表达。此外，它们表达CD80、主要组织相容性复合体II类以及前列腺素D2受体CD294，这些通常都与其他细胞谱系相关，这反映了功能重编程。它们总磷酸酪氨酸水平降低，反映了激活后阶段，以及磷酸化S6核糖体蛋白水平升高，这是一个关键的合成代谢开关，进一步强化了这一概念。因此，我们在CF气道中鉴定出了一个具有存活但功能失调表型的中性粒细胞亚群。这个亚群提供了一个可能的治疗靶点，并表明需要重新审视当前CF气道疾病的范式。
