Neutrophil extracellular traps can serve as platforms for processing and activation of IL‐1 family cytokines

• Published in: The FEBS journal Vol. 284; no. 11; pp. 1712 - 1725
• Main Authors: Clancy, Danielle M., Henry, Conor M., Sullivan, Graeme P., Martin, Seamus J.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2017
• Subjects: Antiinfectives and antibacterials; Cathepsin G; Cathepsin G - metabolism; Cell activation; Cell death; Chromatin; Cytokines; Cytoplasmic Granules - enzymology; Decoration; Deoxyribonuclease I - pharmacology; Deoxyribonucleic acid; DNA; Elastase; Extracellular Traps - enzymology; Extracellular Traps - physiology; Extrusion; Histones; Humans; IL‐1 family; IL‐1α, IL‐36; Inflammation; Inflammation - blood; Interleukin 1; Interleukin-1 - metabolism; Interleukin-1alpha - metabolism; Leukocyte Elastase - metabolism; Leukocytes (neutrophilic); Microorganisms; Mortality; Myeloblastin - metabolism; NETs; Neutrophil Activation - drug effects; neutrophil extracellular traps; Neutrophils; Platforms; Position (location); protease; Proteins; Recombinant Proteins - metabolism; Temporal variations; Tetradecanoylphorbol Acetate - pharmacology; elastase; protease; NETs; neutrophil extracellular traps; IL-1α, IL-36; inflammation; IL-1 family; cathepsin G
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14075

Activated neutrophils can undergo a mode of regulated cell death, called NETosis, that results in the extrusion of chromatin into the extracellular space, thereby acting as extracellular traps for microorganisms. Neutrophil‐derived extracellular traps (NETs) are comprised of DNA decorated with histones, antimicrobial proteins and neutrophil granule proteases, such as elastase and cathepsin G (Cat G). NET‐associated factors are thought to enhance the antimicrobial properties of these structures and localisation of antimicrobial molecules on NETs may serve to increase their local concentration. Because neutrophil‐derived proteases have been implicated in the processing and activation of several members of the extended interleukin (IL)‐1 family, we wondered whether neutrophil NETs could also serve as platforms for the activation of proinflammatory cytokines. Here, we show that neutrophil NETs potently processed and activated IL‐1α as well as IL‐36 subfamily cytokines through NET‐associated Cat G and elastase. Thus, in addition to their role as antimicrobial traps, NETs can also act as local sites of cytokine processing and activation. Activated neutrophils form web‐like structures composed of DNA and associated proteins, called neutrophil extracellular traps (NETs), to entrap and kill microorganisms. Here, we show that neutrophil NETs can process and activate interleukin (IL)‐1α and all three IL‐36 subfamily cytokines through NET‐associated cathepsin G and elastase. Thus, in addition to their role as antimicrobial traps, NETs can also act as platforms for processing and activation of extracellular cytokines such as members of the extended IL‐1 cytokine family.