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

Bárbara Nery Porto,Renato Tetelbom Stein

doi:10.3389/fimmu.2016.00311

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.

Highlights

Neutrophils are key players in microbial killing, being the first immune cells to achieve the site of injury or infection [1]
Aside from these traditional mechanisms, neutrophils are able to extrude DNA lattices, NETs in Pulmonary Diseases called neutrophil extracellular traps (NETs), which entrap and facilitate the killing of bacteria, fungi, protozoa, and even viruses [3,4,5,6,7,8]
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

Summary

Introduction

Neutrophils are key players in microbial killing, being the first immune cells to achieve the site of injury or infection [1]. Many of the microorganisms that colonize CF airways have been shown to induce NET formation directly [4, 6, 12, 37, 38], pro-inflammatory cytokines and neutrophil chemokines present in CF lungs are able to stimulate NET release [30, 33], perpetuating the inflammation. DNase was effective to dismantle non-typeable H. influenzaeinduced MET and NET formation [118], which could be used as a short-term adjunctive therapy to avoid the injurious effects of these extracellular traps and associated proteases during pneumonia and other lung diseases.

Results

Conclusion