Neutrophil Extracellular Traps Contain Calprotectin, a Cytosolic Protein Complex Involved in Host Defense against Candida albicans

By C. Urban, David Ermert, M. Schmid, Ulrike Abu-Abed, C. Goosmann, W. Nacken, V. Brinkmann, P. Jungblut, Arturo Zychlinsky. PLoS Pathogens, 2009

1,639 citations recorded by the source corpus.

Neutrophils are the first line of defense at the site of an infection. They encounter and kill microbes intracellularly upon phagocytosis or extracellularly by degranulation of antimicrobial proteins and the release of Neutrophil Extracellular Traps (NETs). NETs were shown to ensnare and kill microbes. However, their complete protein composition and the antimicrobial mechanism are not well understood. Using a proteomic approach, we identified 24 NET-associated proteins. Quantitative analysis of these proteins and high resolution electron microscopy showed that NETs consist of modified nucleosomes and a stringent selection of other proteins. In contrast to previous results, we found several NET proteins that are cytoplasmic in unstimulated neutrophils. We demonstrated that of those proteins, the antimicrobial heterodimer calprotectin is released in NETs as the major antifungal component. Absence of calprotectin in NETs resulted in complete loss of antifungal activity in vitro. Analysis of three different Candida albicans in vivo infection models indicated that NET formation is a hitherto unrecognized route of calprotectin release. By comparing wild-type and calprotectin-deficient animals we found that calprotectin is crucial for the clearance of infection. Taken together, the present investigations confirmed the antifungal activity of calprotectin in vitro and, moreover, demonstrated that it contributes to effective host defense against C. albicans in vivo. We showed for the first time that a proportion of calprotectin is bound to NETs in vitro and in vivo.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/16e410ed0c17db182ebabc8c92ee4179118f22dc

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Citations in the corpus

Functions of S100 Proteins (2012, background): “NETs are chromatin fibers (histones and DNA) bound with antimicrobial proteins that deliver high local concentrations to pathogens [162].”
Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps (2010, background): “…are composed of decondensed chromatin and antimicrobial factors, including neutrophil elastase (NE) and myeloperoxidase (MPO; Brinkmann et al., 2004; Urban et al., 2009), and capture and kill bacteria, fungi, and parasites (Urban et al., 2006; GuimarãesCosta et al., 2009; Ramos-Kichik et al. 2009).”
Neutrophils, from marrow to microbes. (2010, background): “primarily the cationic (thus, DNA-binding) bactericidal proteins: histones, defensins, elastase, proteinase 3, heparin binding protein, cathepsin G, lactoferrin, and myeloperoxidase (Urban et al., 2009), but also the pattern recognition molecule Pentraxin 3, is NET associated (Jaillon et al.”
Thrombosis: tangled up in NETs. (2014, background): “Central to the feasibility of NETs degradation is their structure: they are strands of highly decondensed chromatin exposed to the extracellular environment and thus accessible to DNases.”
Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality (2011, neutral): “(2) Neutrophils isolated from neonates do not generate as much NETs as neutrophils from adults do, despite a similar induction of superoxide production(59) (3) Stimulation of neutrophils with fMLP, a potent inducer of NADPH oxidase activity, does not induce NETosis.(12,13) (4) The pro-inflammatory s”
NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis (2013, methodology): “Scien NETs by proteomic analyses by us and other groups (25), whereas it is readily identified in these structures by other techniques (14).”
Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones (2012, background): “Inhibition of myeloperoxidase reduces NET-induced cytotoxicity One of the other granular components of NET is myeloperoxidase (MPO) [5,7].”
NETosis: how vital is it? (2013, background): “This mechanism involved DNA-dependent killing and calprotectin, but not histones.(71,81) NET chelation of cations may also contribute to the killing of the opportunistic pathogen P aeruginosa.”