title: An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans.
abstract: The armament of neutrophil-mediated host defense against pathogens includes the extrusion of a lattice of DNA and microbicidal enzymes known as neutrophil extracellular traps (NETs). The receptor/ligand interactions and intracellular signaling mechanisms responsible for elaborating NETs were determined for the response to Candida albicans. Because the host response of extravasated neutrophils to mycotic infections within tissues necessitates contact with extracellular matrix, this study also identified a novel and significant regulatory role for the ubiquitous matrix component fibronectin (Fn) in NET release. We report that recognition of purified fungal pathogen-associated molecular pattern β-glucan by human neutrophils causes rapid (≤ 30 min) homotypic aggregation and NET release by a mechanism that requires Fn. Alone, immobilized β-glucan induces reactive oxygen species (ROS) production but not NET release, whereas in the context of Fn, ROS production is suppressed and NETs are extruded. NET release to Fn with β-glucan is robust, accounting for 17.2 ± 3.4% of total DNA in the cell population. Release is dependent on β-glucan recognition by complement receptor 3 (CD11b/CD18), but not Dectin-1, or ROS. The process of NET release included filling of intracellular vesicles with nuclear material that was eventually extruded. We identify a role for ERK in homotypic aggregation and NET release. NET formation to C. albicans hyphae was also found to depend on β-glucan recognition by complement receptor 3, require Fn and ERK but not ROS, and result in hyphal destruction. We report a new regulatory mechanism of NETosis in which the extracellular matrix is a key component of the rapid antifungal response.
authors.affiliation: Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Angel S
authors.initials: AS
authors.lastname: Byrd
authors.forename: Xian M
authors.initials: XM
authors.lastname: O'Brien
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Johnson
authors.forename: Liz M
authors.initials: LM
authors.lastname: Lavigne
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Reichner
mesh_terms: D002176:Candida albicans / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002449:Cell Aggregation / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology* / Q000378:metabolism; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D016177:Macrophage-1 Antigen; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D016897:Respiratory Burst / Q000276:immunology; D013997:Time Factors; D047071:beta-Glucans / Q000378:metabolism
chemical_list: D005353:Fibronectins; D016177:Macrophage-1 Antigen; D017382:Reactive Oxygen Species; D047071:beta-Glucans