Neutrophil extracellular traps are associated with inflammation in chronic airway disease

Abstract

Background and objective: Neutrophil extracellular traps (NETs) are web-like structures comprising DNA and antimicrobial proteins, expelled from neutrophils during NETosis. Persistence of NETs can be proinflammatory, yet their role in respiratory disease remains unclear. This study aimed to investigate the presence of NETs in sputum from patients with asthma and COPD, and the relationship of NETs with inflammatory phenotype and disease severity. Methods: Induced sputum was collected from healthy controls, asthma and COPD patients. Extracellular DNA (eDNA) was quantified by PicoGreen. LL-37, α-defensins1-3, NE, IL-1β and CXCL8 were quantified by ELISA. PAD4 and NLRP3 gene expression was performed using qPCR. NETs were imaged in sputum smears using immunofluorescence microscopy. Results: Sputum eDNA and NET neutrophil antimicrobial proteins were significantly elevated in asthma and COPD compared with healthy controls. Levels of eDNA and NET components were significantly higher in neutrophilic versus non-neutrophilic asthma and COPD. NETs were clearly visualized in sputum smears. PAD4 mRNA was upregulated in neutrophilic COPD. The level of eDNA was higher in severe asthma. High eDNA levels were associated with heightened innate immune responses, including elevated CXCL8 and IL-1β, and NLRP3 gene expression in both COPD and asthma. Antimicrobial proteins and eDNA were positively correlated with airway neutrophils, and negatively correlated with lung function and symptoms. Conclusion: NETs are present in the airways of subjects with asthma and COPD. Accumulation of excessive NETs was associated with activation of innate immune responses contributing to disease pathogenesis in chronic airway disease.

Role of Neutrophil Extracellular Traps in Asthma and Chronic Obstructive Pulmonary Disease

“…[46] It has been found that the level of LPS in asthmatics is elevated, indicating that NETosis might be related to the presence of LPS. [8] In addition, IL-8 is a potential trigger of NETosis in these airways as it has previously been shown to induce NETosis in other studies. [2104849] Côté et al .…”

“…[7] Despite the positive role of NETs in the resistance to infection, one recent study demonstrated that NETs exist in the airways of patients with chronic inflammatory airway diseases. [8] Moreover, the accumulation of NETs is related to the activation of the innate immune response, which contributes to the disease pathogenesis in chronic inflammatory airway diseases. [8] Although it remains unclear how NETs participate in the pathogenesis of chronic inflammatory airway diseases, the significance of NETs in that diseases should not be ignored.…”

“…[8] Moreover, the accumulation of NETs is related to the activation of the innate immune response, which contributes to the disease pathogenesis in chronic inflammatory airway diseases. [8] Although it remains unclear how NETs participate in the pathogenesis of chronic inflammatory airway diseases, the significance of NETs in that diseases should not be ignored. This article provides an overview of the recent advances in NETs research, including the composition and functionality of NETs, as well as their relationship with asthma and COPD [Figure 1].…”

Neutrophil extracellular traps as the main source of eDNA

“…Interestingly, the formation of bundles induced by F-actin, DNA or bacteriophages is diminished for synthetic analogues of CAPs, such as ceragenins, which maintain their high antibacterial activity despite the presence of PE at the infection site [46,47]. Importantly, elevated eDNA and NET levels and their accumulation in biological fluids is a factor activating innate immune responses, which considerably affect the development of such diseases as asthma and chronic obstructive pulmonary disease [48], periodontitis [49], antineutrophil cytoplasmic antibody-associated vasculitis (AAV) [29], or cancerassociated thrombosis [50]. Quantitative analysis of the physical chemistry of polyelectrolytes has been useful for designing possible countermeasures to release endogenous antimicrobial peptides trapped in the polyelectrolyte bundles present in purulent fluids [5,45,[51][52][53][54][55][56].…”

Aberrant function of neutrophils in asthma

“…Accumulating evidences shown that NETs directly contributed to host cell death and chronic tissue damage when formed in excess or were insufficiently cleared by mechanisms that were still poorly understood [34] . Recently, several studies have detected increased NETs and NET components in neutrophils from airways or peripheral blood of patients with asthma, suggesting an involvement of NETs in asthma pathogenesis [35][36][37] . Accumulation of excessive NETs contributed to the persistent airway neutrophilia and enhanced asthma severity by damaging airway epithelium and triggering inflammatory responses of human airway epithelial cells and eosinophils [35] .…”