Double-Edged Swords of Innate Immunity Neutrophil Extracellular Traps
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Neutrophil Extracellular Traps: Double-Edged Swords of Innate Immunity Mariana J. Kaplan and Marko Radic This information is current as J Immunol 2012; 189:2689-2695; ; of September 26, 2021. doi: 10.4049/jimmunol.1201719 http://www.jimmunol.org/content/189/6/2689 Downloaded from References This article cites 77 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/189/6/2689.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Neutrophil Extracellular Traps: Double-Edged Swords of Innate Immunity Mariana J. Kaplan* and Marko Radic† Spectacular images of neutrophils ejecting nuclear chro- has important chemotactic and immunostimulatory effects, as matin and bactericidal proteins, in response to mi- discussed below (1). crobes, were first reported in 2004. As externalized The mechanisms used by neutrophils to eliminate microbes chromatin could entangle bacteria, these structures were include phagocytosis, generation of reactive oxygen species named neutrophil extracellular traps (NETs). Subse- (ROS), and the release of microbicidal molecules from quent studies identified microorganisms and sterile granules (degranulation). In 2004, another distinct antimi- conditions that stimulate NETs, as well as additional crobial activity was described: neutrophils extrude a meshwork cell types that release extracellular chromatin. The re- of chromatin fibers that are decorated with granule-derived Downloaded from lease of NETs is the most dramatic stage in a cell death antimicrobial peptides and enzymes such as neutrophil elas- process called NETosis. Experimental evidence suggests tase (Fig. 1), cathepsin G, and myeloperoxidase (MPO) (2). that NETs participate in pathogenesis of autoimmune These structures, called neutrophil extracellular traps (NETs), represent an important strategy to immobilize and kill in- and inflammatory disorders, with proposed involve- vading microorganisms. The NET scaffold consists of chro- ment in glomerulonephritis, chronic lung disease, sep- matin fibers with a diameter of 15–17 nm; DNA and histones http://www.jimmunol.org/ sis, and vascular disorders. Exaggerated NETosis or represent the major NET constituents (2). Mass spectrometry diminished NET clearance likely increases risk of auto- has identified various additional proteins associated with reactivity to NET components. The biological signifi- NETs, including components from various types of granules. cance of NETs is just beginning to be explored. A Although conserved proteins are found in extracellular trap more complete integration of NETosis within immu- fractions, it is still unclear whether the peptide composition of nology and pathophysiology will require better under- these structures may vary depending on the specific stimulus standing of NET properties associated with specific that promotes NET formation (3, 4). disease states and microbial infections. This may lead The putative role of extracellular traps in host defense is by guest on September 26, 2021 to the identification of important therapeutic tar- exemplified by their conserved nature in various vertebrates gets. The Journal of Immunology, 2012, 189: 2689– (5–8), insects (9) and even plants (10). Whereas the initial 2695. observation of NET formation placed the process within the context of innate immune responses to infections, recent evidence suggests that these structures also figure promi- eutrophils are the most abundant leukocytes in mam- nently at the center of various pathologic states. As such, mals and, as a first line of defense against microbes, NETs may function as double-edged swords, serving as ef- N they play crucial roles in innate immune responses. fective antimicrobial defenses, but also as putative sources of The homeostasis of neutrophils is maintained by balancing molecules with immune effector and proinflammatory roles their short lifespan in the circulation with their regulated that, in susceptible individuals, may promote tissue damage release from the bone marrow. Neutrophils have various types and autoimmunity. Furthermore, other granulocytes (mast of granules, containing hundreds of proteins. These include cells and eosinophils) can form extracellular traps upon bactericidal proteins, some of them with important effects on stimulation, a process thus renamed as ETosis (11, 12). In innate and adaptive immune responses, such as a-defensins, the case of eosinophils, NET-like structures containing mi- the cathelicidin human cationic antimicrobial protein of 18 tochondrial DNA and granular proteins have been proposed kDa, and lactoferrin, among others. LL-37, a proteolytic to contribute to host defense and to allergic responses (12, product of human cationic antimicrobial protein of 18 kDa, 13). *Division of Rheumatology, Department of Internal Medicine, University of Michigan School, 1150 W. Medical Center Drive, 5520 Medical Science Research Building-I, Medical School, Ann Arbor, MI 48109; and †Department of Microbiology, Immunol- Ann Arbor, MI 48109-5680. E-mail address: [email protected] ogy and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN Abbreviations used in this article: ANCA, anti-neutrophil cytoplasmic Ab; CGD, 38163 chronic granulomatous disease; EC, endothelial cell; MPO, myeloperoxidase; NET, Received for publication June 21, 2012. Accepted for publication July 27, 2012. neutrophil extracellular trap; PAD4, peptidylarginine deiminase 4; pDC, plasmacytoid dendritic cell; PKC, protein kinase C; ROS, reactive oxygen species; SLE, systemic lupus This work was supported by the National Institutes of Health through Public Health erythematosus. Service Grant HL088419 (to M.J.K.) and by the Lupus Research Institute of New York (to M.R.). Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 Address correspondence and reprint requests to Dr. Mariana J. Kaplan, Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical www.jimmunol.org/cgi/doi/10.4049/jimmunol.1201719 2690 BRIEF REVIEWS: NETs AND IMMUNOLOGY forming NETs upon stimulation. When comparing mouse and human neutrophils, murine cells make NETs more slowly and less efficiently and these structures have more compact ap- pearance than do human cells (5). Most studies of NETs in mice use bone marrow neutrophils, whereas the preferred source in humans is peripheral blood. This may account for some differences identified between these species. Microbes and NETs An astounding variety of microbes induce NET formation (2, 29–35). NET-inducing stimuli include whole bacteria as well as cell surface components of Gram-positive and Gram- FIGURE 1. Representative images of NETs induced in vitro by LPS in negative bacterial lipoteichoic acid and LPS, as well as break- human neutrophils. NETs are visualized by costaining of neutrophil elastase down products of prokaryotic proteins, such as fMLP (18). (green) and nuclear material (DAPI, blue). Original magnification 340. Notable examples of bacteria that potently induce NETs in- clude Staphylococcus aureus (36, 37), Streptococcus sp. (29, 38), Two models for NET release have been proposed. In the first Haemophilus influenzae (30), Klebsiella pneumoniae (39), Lis- model, NETosis, a distinct form of active cell death, is char- teria monocytogenes (40), Mycobacterium tuberculosis (31), and Downloaded from acterized by release of decondensed chromatin and granular Shigella flexneri (2). Other examples include pathogens such as contents to the extracellular space. During NETosis, nuclear Yersinia (41) and members of the oral microbiome, including and granular membranes dissolve, and nuclear contents de- Porphyromonas gingivalis (33). condense into the cytoplasm. This is followed by plasma mem- Neutrophils from neonates, compared with adult neutro- brane rupture and release of chromatin decorated with granu- phils, are less capable of forming NETs in response to various lar proteins into the extracellular space (2, 14, 15). In contrast microbial stimuli, a phenomenon that may contribute to the http://www.jimmunol.org/ to apoptotic cells, netting neutrophils do not appear to dis- enhanced susceptibility to infections observed in this age group play “eat me” signals, and this may prevent their clearance (42). Containment of microbial pathogens to sites of initial by phagocytes. Indeed, NETs are disassembled primarily by infection may be an important function of NETs. Indeed, nucleases (15). The second model involves a DNA/serine staphylococci and streptococci express virulence factors that protease extrusion mechanism from intact neutrophils, where degrade extracellular traps and may free the bacterium