Transcriptional reprogramming drives neutrophil phenotype and function in chronic lung disease

作者：Camilla Margaroli, Diego Moncada Giraldo, Dalia Arafat-Gulick, Brian Dobosh, Vincent D. Giacalone, Haydn Kissick, Osric Forrest, Chunhui Gu, Gregory Gibson, Rabindra Tirouvanziam · 发表于：The Journal of Immunology · 年份：2020 · DOI：10.4049/jimmunol.204.supp.148.39 · 研究领域：Immune Response and Inflammation、Neonatal Respiratory Health Research、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Abstract Rationale Neutrophils are often considered the first line of defense against bacterial infections. In cystic fibrosis (CF), massive neutrophil presence is concomitant with phenotypical changes and prolonged bacterial infections. Here, we sought to determine whether this paradox was dependent on transcriptional reprogramming of airway neutrophils. Methods Blood neutrophils were transmigrated in an in vitro model recapitulating the in vivo phenotype of CF airway neutrophils. Blood and airway neutrophils from the in vitro model and from CF patients were analyzed by flow cytometry, microarrays and RNA sequencing, as well as used for bacterial killing assays. Results Airway neutrophils in vivo and in vitro showed increased total RNA content and profound shifts in their transcriptional profile for survival, anabolic, and antimicrobial genes. Furthermore, transcriptional blockade by α-amanitin in airway neutrophils in vitro and ex vivo fully restored their bacterial killing capacity. Conclusions These findings show that some canonical functions in neutrophils, including bacterial clearance, depend on the active repression of RNA transcription, which can be modulated by the local microenvironment at the site of inflammation, challenging the paradigm holding these cells as terminally differentiated.