Transcriptional firing represses bactericidal activity in cystic fibrosis airway neutrophils

Margaroli, Camilla; Moncada-Giraldo, Diego; Gulick, Dalia Arafat; Dobosh, Brian; Giacalone, Vincent D.; Forrest, Osric A.; Sun, Fangxu; Gu, Chunhui; Gaggar, Amit; Kissick, Haydn; Wu, Ronghu; Gibson, Greg; Tirouvanziam, Rabindra

Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacterial infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of anabolic genes and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Treatment by the RNA polymerase II and III inhibitor α-amanitin restores the expression of key antimicrobial genes and increases the bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the site of inflammation via RNA and protein synthesis, leading to adaptations that affect their canonical functions (i.e., bacterial clearance).