Sputum from patients with primary ciliary dyskinesia contains high numbers of dysfunctional neutrophils and inhibits efferocytosis

Abstract

Background Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by recurrent airway infection and inflammation. There is no cure for PCD and to date there are no specific treatments available. Neutrophils are a crucial part of the immune system and are known to be dysfunctional in many inflammatory diseases. So far, the role of the neutrophils in PCD airways is largely unknown. The purpose of this study was to investigate the phenotype and function of airway neutrophils in PCD, and compare them to blood neutrophils. Methods Paired peripheral blood and spontaneously expectorated sputum samples from patients with PCD (n = 32) and a control group of patients with non-PCD, non-cystic fibrosis bronchiectasis (n = 5) were collected. The expression of neutrophil-specific surface receptors was determined by flow cytometry. Neutrophil function was assessed by measuring the extent of actin polymerization, production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs) in response to activating stimuli. Results Sputum neutrophils displayed a highly activated phenotype and were unresponsive to stimuli that would normally induce ROS production, actin polymerization and the expulsion of NETs. In addition, PCD sputum displayed high activity of neutrophil elastase, and impaired the efferocytosis by healthy donor macrophages. Conclusions Sputum neutrophils in PCD are dysfunctional and likely contribute to ongoing inflammation in PCD airways. Further research should focus on anti-inflammatory therapies and stimulation of efferocytosis as a strategy to treat PCD.

Histologic characterization of primary ciliary dyskinesia chronic rhinosinusitis

“…Peripheral blood neutrophils showed reduced migration toward CXCL8, and sputum neutrophils exhibited decreased reactive oxygen species release and impaired efferocytosis in PCD patients. 10 Therefore, it is possible that the elevated neutrophil count in the sinus mucosa of the PCD cohort might result from the stasis of dysfunctional neutrophils by its impaired migratory mechanisms.…”

Airway specific deregulation of asthma-related serpins impairs tracheal architecture and oxygenation in D. melanogaster

“…Proteases are key elements of the airway epithelial host defence and are tightly regulated by anti-proteases to prevent lung damage from an overshooting proteolytic activity. In line, an enhanced proteolytic activity has been described for a majority of chronic lung diseases such as asthma 4 – 7 , chronic obstructive pulmonary disease (COPD) 8 , 9 , cystic fibrosis (CF) 10 , 11 , non-CF bronchiectasis 12 , 13 and primary ciliary dyskinesia 14 – 16 . Among anti-proteases, serpins constitute the largest family and are found in almost all organisms 17 .…”

Redox Imbalance in Nasal Epithelial Cells of Primary Ciliary Dyskinesia Patients

“…These neutrophils release multiple proteases and generate substantial quantities of reactive oxygen and nitrogen species (ROS and RNS, respectively). The increased levels of ROS and RNS contribute to an environment that has the potential to eliminate agents causing inflammation [3].…”