Abstract
Neutrophils act as the first line of defense during infection and inflammation. Once activated, they are able to fulfil numerous tasks to fight inflammatory insults while keeping a balanced immune response. Besides well-known functions, such as phagocytosis and degranulation, neutrophils are also able to release “neutrophil extracellular traps” (NETs). In response to most stimuli, the neutrophils release decondensed chromatin in a NADPH oxidase-dependent manner decorated with histones and granule proteins, such as neutrophil elastase, myeloperoxidase, and cathelicidins. Although primarily supposed to prevent microbial dissemination and fight infections, there is increasing evidence that an overwhelming NET response correlates with poor outcome in many diseases. Lung-related diseases especially, such as bacterial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease, aspergillosis, influenza, and COVID-19, are often affected by massive NET formation. Highly vascularized areas as in the lung are susceptible to immunothrombotic events promoted by chromatin fibers. Keeping this fragile equilibrium seems to be the key for an appropriate immune response. Therapies targeting dysregulated NET formation might positively influence many disease progressions. This review highlights recent findings on the pathophysiological influence of NET formation in different bacterial, viral, and non-infectious lung diseases and summarizes medical treatment strategies.
Highlights
The lung comprises different mucosal and alveolar compartments harboring resident immune cells maintaining a well-balanced milieu of protection versus potentially infectious inhaled pathogens
Long persisting S. aureus has been shown to be able to adapt to neutrophil-rich environments by increasing nuclease expression to evade neutrophil extracellular traps (NETs) killing, as it was demonstrated in airway isolates of cystic fibrosis patients [139]
The authors in this study showed that treatment with sialidase or the use of P. aeruginosa strains lacking sialic acids led to increased NET production compared with sialic acidpositive strains
Summary
The lung comprises different mucosal and alveolar compartments harboring resident immune cells maintaining a well-balanced milieu of protection versus potentially infectious inhaled pathogens. NETs are able to promote vaso-occlusion, initiated by the hypoxia-induced release of von Willebrand factor (VWF) and endothelial P-selectin, resulting in neutrophil recruitment and activation [35,36]. Another proposed mechanism is the P-selectin-dependent neutrophil and platelet recruitment. In vitro experiments with human monocyte-derived macrophages and PMA-stimulated human neutrophils demonstrated that macrophages are able to internalize NETs in a cathelicidin LL37-dependent manner and degrade DNA via TREX1/DNAseIII. In this setting, DCs contribute to extracellular. This review focuses on the role of NET formation during virus-induced lung infections, as well as primary and secondary bacterial infections, and summarizes possible therapeutic interventions
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