Aberrant immune programming in neutrophils in cystic fibrosis

Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the gene that encodes Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride and bicarbonate channel. Persistent neutrophilic inflammation is a major contributor to CF lung disease. However, how CFTR loss-of-function leads to excessive inflammation and its clinical sequela remains incompletely understood. In this study, neutrophils from F508del-CF and healthy control (HC) participants were compared for gene transcription. We found that CF circulating neutrophils have a prematurely-primed basal state with significantly higher scores for activation, chemotaxis, immune signaling, and pattern recognition. Such an irregular basal state appeared not related to the blood environment, and was also observed in neutrophils derived from F508del-CF HL-60 cell line, indicating an innate characteristic of the phenotype. LPS stimulation drastically shifted the transcriptional landscape of HC neutrophils towards a robust immune response; however, CF neutrophils were immune-exhausted, reflected by abnormal cell aging and fate determination in gene programming. Moreover, CF sputum neutrophils differed significantly from CF circulating neutrophils in gene transcription with increased inflammatory response, aging, apoptosis and necrosis, suggesting additional environmental influences on the neutrophils in CF lungs. Taken together, our data indicate that loss of CFTR function has intrinsic effects on neutrophil immune programming, leading to premature priming and dysregulated response to challenge.