Neutrophil Extracellular Traps in ANCA-Associated Vasculitis and Interstitial Lung Disease: A Scoping Review

Abstract

Background: Deregulated neutrophil extracellular traps (NETs) formation is implicated in various diseases, including ANCA-associated vasculitis and pulmonary fibrosis (PF). Lung involvement is frequent in AAV, and interstitial lung diseases (ILDs) are strongly related to MPO-ANCA positivity and mainly reported in microscopic polyangiitis. The association between AAV and ILD is a strong indicator of poor prognosis and limited survival. Neutrophils, ANCA and NET interplay in PF development in AAV. This study aimed to review the literature concerning the implications of NET in lung fibrogenesis specifically focused on AAV associated with ILD, and the potential of NET as a theranostic marker. Methods: Through scoping review methodology, we used a descriptive thematic analysis to understand the pathogenic role of NETs in patients with AAV and pulmonary fibrosis and their further role as a theranostic marker of this disease. Results: The implications of NET in the pathogenesis of AAV and ILD, as well as an association between these two diseases, have been identified, but the underlying pathophysiological mechanisms are still unknown. The pharmacological or genetic inhibition of NET release reduces disease severity in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. In this regard, despite the lack of clinical data, we may hypothesise that an optimal management of AAV-ILD patients would require not only B-cells targeted therapy, but also NETs inhibition. Conclusion: Preliminary findings seem to display a lack of efficacy of traditional immunosuppressants, such as Rituximab, in this subset of patients, while to date no patients suffering from a definite ILD have been enrolled in clinical trials. Further insights would be provided by their employment, as a combination treatment, in common clinical practice. Although we can imagine that the inhibition of NETs in patients with AAV-ILD could reduce severity and mortality, we still lack the scientific basis that could improve our understanding of the disease from a molecular point of view.

Interstitial lung disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis: an update on pathogenesis and treatment

“…Activated neutrophils might in turn contribute to lung fibrosis through the release of neutrophil extracellular traps (NETs) [21]. Deregulated NET production has been implicated in the pathogenesis of AAV and might induce lung fibrosis by promoting the activity of fibroblasts and profibrotic cytokines in the interstitial lung space [22 ▪▪ ]. NETs are also thought to contribute to vessel inflammation by damaging endothelial cells and promoting complement activation.…”

C-X-C-Chemokine-Receptor-Type-4 Inhibitor AMD3100 Attenuates Pulmonary Inflammation and Fibrosis in Silicotic Mice

“…Other in vitro studies support our results by showing that NETs are formed in response to sterile inflammation. In addition, NETs were reported to induce epithelial and endothelial cell death and cause lung destruction, 40 promoting the activation of fibroblasts and their differentiation into myofibroblasts, which can contribute to pulmonary fibrosis. 20 , 41 Therefore, neutrophils play pro-inflammatory and pro-fibrotic roles in silicosis.…”

Short-Term Effect of SARS-CoV-2 Spike Protein Receptor-Binding Domain-Specific Antibody Induction on Neutrophil-Mediated Immune Response in Mice

“…While APA are associated with thrombocytopenia, ANA can be responsible for the vasculitis in COVID-19 complications [ 39 , 40 ]. Interestingly, anti-neutrophil cytoplasmic antibodies (ANCA), directed against proteins of neutrophil cytoplasmic granules, were detected in COVID-19 patients [ 41 , 42 ]. ANCA can be induced by the NET remnants.…”