NET balancing: a problem in inflammatory lung diseases

Abstract

Neutrophil extracellular traps (NETs) are beneficial antimicrobial defense structures that can help fight against invading pathogens in the host. However, recent studies reveal that NETs exert adverse effects in a number of diseases including those of the lung. Many inflammatory lung diseases are characterized with a massive influx of neutrophils into the airways. Neutrophils contribute to the pathology of these diseases. To date, NETs have been identified in the lungs of cystic fibrosis (CF), acute lung injury (ALI), allergic asthma, and lungs infected with bacteria, virus, or fungi. These microbes and several host factors can stimulate NET formation, or NETosis. Different forms of NETosis have been identified and are dependent on varying types of stimuli. All of these pathways however appear to result in the formation of NETs that contain DNA, modified extracellular histones, proteases, and cytotoxic enzymes. Some of the NET components are immunogenic and damaging to host tissue. Innate immune collectins, such as pulmonary surfactant protein D (SP-D), bind NETs, and enhance the clearance of dying cells and DNA by alveolar macrophages. In many inflammatory lung diseases, bronchoalveolar SP-D levels are altered and its deficiency results in the accumulation of DNA in the lungs. Some of the other therapeutic molecules under consideration for treating NET-related diseases include DNases, antiproteases, myeloperoxidase (MPO) inhibitors, peptidylarginine deiminase-4 inhibitors, and anti-histone antibodies. NETs could provide important biological advantage for the host to fight against certain microbial infections. However, too much of a good thing can be a bad thing. Maintaining the right balance of NET formation and reducing the amount of NETs that accumulate in tissues are essential for harnessing the power of NETs with minimal damage to the hosts.

Keywords: acute lung injury (ALI); cystic fibrosis (CF); lung infection; lung inflammation; neutrophil; neutrophil extracellular traps (NETs); surfactant protein D (SP-D).

Figure 1

NETs in infected and inflamed airways. Lungs respond to sterile injury or infection by secreting various signaling molecules. During infection and inflammation, various cells (e.g., endothelial, epithelial, immune cells) express inflammatory cytokines, chemokines, and growth factors to recruit monocytes (e.g., MCP-1) and neutrophils [e.g., IL-8 (KC/MIP-2)] into the airway lumen. Neutrophils can be stimulated by a variety of agents (e.g., bacteria, viruses, fungi, protozoa, LPS, singlet oxygen, PMA, GM-CSF+C5a) to undergo NETosis. Release of cytotoxic DNA–protein complexes [e.g., citrullinated histone (CitH₃), neutrophil elastase (NE), myeloperoxidase (MPO), cathelicidin, other neutrophil proteases] not only increase mucus viscosity, but also contribute to lung damage that can perpetuate the vicious cycle of lung injury and inflammation. NETs are considered to be degraded by DNase enzymes. Macrophages can also internalize and remove DNA, as well as other cellular debris. A balance between NETosis and NET clearance is essential for effectively clearing infectious agents with minimal damage to the lungs. Dysregulation in these two processes can lead to lung injury and exacerbation of lung diseases. Innate immune collectins could help to maintain healthy lungs with minimal inflammation. SP-A, pulmonary surfactant protein A; SP-D, pulmonary surfactant protein D. PMN, neutrophils; MΦ, macrophages. Inflamed airways also have excess mucus. The putative sequence of NETotic events in the lungs are numbered as 1, 2, and 3. Note: Cytokines, chemokines, and growth factors are placed near their most probable source of secretion. However, the source and/or degree of cytokine secretion varies depending on the stimuli.