Abstract
Cystic fibrosis patients suffer from chronic lung infection and inflammation due to the secretion of viscous sputum. Sputum viscosity is caused by extracellular DNA, some of which originates from the release of neutrophil extracellular traps (NETs). During NET formation neutrophil elastase (NE) partially processes histones to decondense chromatin. NE is abundant in CF sputum and is thought to contribute to tissue damage. Exogenous nucleases are a palliative treatment in CF as they promote sputum solubilization. We show that in a process reminiscent of NET formation, NE enhances sputum solubilization by cleaving histones to enhance the access of exogenous nucleases to DNA. In addition, we find that in Cf sputum NE is predominantly bound to DNA, which is known to downregulate its proteolytic activity and may restrict host tissue damage. The beneficial role of NE in CF sputum solubilization may have important implications for the development of CF therapies targeting NE.
Highlights
Cystic fibrosis (CF) is a debilitating hereditary disease that often results in early death of the affected individuals
neutrophil extracellular traps (NETs) are present in cystic fibrosis sputum We first examined CF sputum derived from 3 CF patients who were not undergoing DNase therapy, for the presence of NETs or neutrophils undergoing NET formation by immunofluorescence microscopy
A fraction of histone H3 migrated with DNA that was not bound to MPO or neutrophil elastase (NE) (Fig. 2a). Some of these DNA fragments may derive from NET material as MPO is thought to be unevenly distributed in the chromatin of NETs [8]. These findings suggest that a significant portion of chromatin in CF sputum may originate from NET formation
Summary
Cystic fibrosis (CF) is a debilitating hereditary disease that often results in early death of the affected individuals. CF sputum contains DNA, neutrophil elastase (NE), myeloperoxidase (MPO) and other neutrophil proteins [5]. Neutrophil granular proteins are thought to be released through degranulation, the origin of the extracellular DNA is not well established. The extracellular DNA was suspected to originate from necrotic neutrophils and lung tissues rather than infecting bacteria [6]. CF sputum was found to contain neutrophil extracellular traps (NETs) [7]. NETs are composed of decondensed chromatin in complex with neutrophil antimicrobial proteins (NETs) [8,9] that are released by dying neutrophils [10] in order to trap and kill microbes [8,11]. NET release may account for a significant portion of the extracellular DNA and azurophilic granule proteins found in CF sputum
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