Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review

Abstract

BackgroundCystic Fibrosis (CF) is a devastating genetic disease characterised primarily by unrelenting lung inflammation and infection resulting in premature death and significant morbidity. Neutrophil Extracellular Traps (NETs) are possibly key to inflammation in the disease. This review aims to draw together existing research investigating NETs in the context of a dysfunctional innate immune system in CF.Main bodyNETs have a limited anti-microbial role in CF and studies have shown they are present in higher numbers in CF airways and their protein constituents correlate with lung function decline. Innate immune system cells express CFTR and myeloid-specific CFTR KO mice have greater neutrophil recruitment and higher pro-inflammatory cytokine production to both sterile and bacterial inflammatory challenges. CFTR KO neutrophils have impaired anti-microbial capacity and intrinsic abnormalities in the pH of their cytoplasm, abnormal protein trafficking, increased neutrophil elastase and myeloperoxidase function, and decreased hypochlorite concentrations in their phagolysosomes. Furthermore, neutrophils from CF patients have less intrinsic apoptosis and may be therefore more likely to make NETs. CFTR KO macrophages have high intraphagolysosomal pH and increased toll-like receptor 4 on their cell surface membranes, which inhibit their anti-microbial capacity and render them hyper-responsive to inflammatory stimuli, respectively. Pharmacological treatments for CF target these intrinsic abnormalities of immune dysfunction. Emerging evidence suggests that the absence of CFTR from neutrophils affects NETosis and the interaction of NETs with macrophages.ConclusionCurrent evidence suggests that NETs contribute to inflammation and lung destruction rather than working effectively in their anti-microbial capacity. Further studies focussing on the pro-inflammatory nature of NET constituents are required to identify the exact mechanistic role of NETs in CF and potential therapeutic interventions.

Inflammation in cystic fibrosis: An update

“…CF neutrophils often undergo necrosis rather than apoptosis leading to the formation of NETs (NETosis). Although NETosis is a form of cell death, neutrophils can also release NETs by a process known as “vital NETosis.” NETs form a mesh‐like network that consists of neutrophil chromatin complexed with histones, pro‐inflammatory mediators, and neutrophil granule contents . The majority of human DNA present in the CF airway actually arises from NETs .…”

Viral strategies predisposing to respiratory bacterial superinfections

“…95 NETs are a mesh-like network composed of cytosolic and granule proteins that are assembled on a scaffold of decondensed chromatin. 95 Although the majority of DNA in NETs originates from the nuclei, these structures also contain mitochondrial DNA. NETs trap, neutralize and kill bacteria, fungi, viruses, and parasites and are thought to prevent bacterial and fungal dissemination.…”

“…95 In CF, however, NETs have the tendency to become ineffectual in killing bacteria over time but do not lose the ability incite a vigorous and damaging response, providing long-lasting proinflammatory stimuli in the airways. [95][96][97] 7 | AIRWAY MICROBIOME prevailed. 104 These data may suggest a possible role of microbiome in the clinical expression of influenza infection and also in the promotion of bacterial superinfections.…”

NETs in pneumonia: is just enough the right amount?

“…NETs have been associated with inflammation in a number of sterile inflammatory conditions such as systemic lupus erythematosus, rheumatoid arthritis, small vessel vasculitis, gout and cardiovascular disease [19], underlining a role for NETs in inflammation, although the role of NETs in the inflammatory response to infection is less well defined. Crucially the mechanisms by which NETs can promote inflammation are now being revealed and recent evidence suggests that the interaction of NETs with macrophages may be key to this [20,21].…”