Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good Thing?

Abstract

Neutrophil extracellular traps (NETs) arise from the release of granular and nuclear contents of neutrophils in the extracellular space in response to different classes of microorganisms, soluble factors, and host molecules. NETs are composed by decondensed chromatin fibers coated with antimicrobial granular and cytoplasmic proteins, such as myeloperoxidase, neutrophil elastase (NE), and α-defensins. Besides being expressed on NET fibers, NE and MPO also regulate NET formation. Furthermore, histone deimination by peptidylarginine deiminase 4 (PAD4) is a central step to NET formation. NET formation has been widely demonstrated to be an effective mechanism to fight against invading microorganisms, as deficiency in NET release or dismantling NET backbone by bacterial DNases renders the host susceptible to infections. Therefore, the primary role of NETs is to prevent microbial dissemination, avoiding overwhelming infections. However, an excess of NET formation has a dark side. The pathogenic role of NETs has been described for many human diseases, infectious and non-infectious. The detrimental effect of excessive NET release is particularly important to lung diseases, because NETs can expand more easily in the pulmonary alveoli, causing lung injury. Moreover, NETs and its associated molecules are able to directly induce epithelial and endothelial cell death. In this regard, massive NET formation has been reported in several pulmonary diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory syncytial virus bronchiolitis, influenza, bacterial pneumonia, and tuberculosis, among others. Thus, NET formation must be tightly regulated in order to avoid NET-mediated tissue damage. Recent development of therapies targeting NETs in pulmonary diseases includes DNA disintegration with recombinant human DNase, neutralization of NET proteins, with anti-histone antibodies and protease inhibitors. In this review, we summarize the recent knowledge on the pathophysiological role of NETs in pulmonary diseases as well as some experimental and clinical approaches to modulate their detrimental effects.

Keywords: NETs; bacteria; lung infection; neutrophil; neutrophil extracellular traps; pulmonary diseases; respiratory infection; viruses.

Figure 1

Overview of the beneficial and detrimental roles of NETs in pulmonary diseases. Infectious and non-infectious pulmonary diseases cause the massive infiltration of neutrophils into the lungs. Activated neutrophils release an excess of NETs in the airways. The production of NETs requires the activation of specific signaling pathways described so far, such as raf-MEK-ERK and p38 MAPK, PAD-4, autophagy and NADPH oxidase-induced ROS generation. Additionally, NE and MPO also regulate NET formation. Accordingly, selective inhibitors of these signaling pathways are able to abolish or decrease NET release. The primary goal of NETs is to protect the host from invading microorganisms through their sticky nature and the high concentrations of antimicrobial proteins. However, these characteristics make NETs potentially detrimental to host cells and tissues. Excessive NET formation enhances mucus viscosity, filling the lungs, and impairing lung function. NET proteins are highly cytotoxic and can induce endothelial and epithelial cell death and cause the disruption of host proteins and cellular matrix.