title: Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation.
abstract: The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10- to 40-nm-sized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100-1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Muñoz
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Danylo Halytsky Lviv National Medical University, 79010 Lviv, Ukraine.
authors.forename: Rostyslav
authors.identifier: 0000-0002-2344-1349
authors.initials: R
authors.lastname: Bilyy
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Mona H C
authors.initials: MH
authors.lastname: Biermann
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kienhöfer
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maueröder
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Hahn
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Brauner
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weidner
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan Province, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Electron Devices, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91058, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Scharin-Mehlmann
authors.affiliation: Section for Experimental Oncology and Nanomedicine, Department of Otorhinolaryngology, Head, and Neck Surgery, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Janko
authors.affiliation: Section for Experimental Oncology and Nanomedicine, Department of Otorhinolaryngology, Head, and Neck Surgery, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Friedrich
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine 3, Nikolaus Fiebiger Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mielenz
authors.affiliation: Danylo Halytsky Lviv National Medical University, 79010 Lviv, Ukraine.
authors.forename: Tetiana
authors.initials: T
authors.lastname: Dumych
authors.affiliation: Danylo Halytsky Lviv National Medical University, 79010 Lviv, Ukraine.
authors.forename: Maxim D
authors.initials: MD
authors.lastname: Lootsik
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schauer
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan Province, China; zhao.y1977@163.com martin.herrmann@uk-erlangen.de.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; zhao.y1977@163.com martin.herrmann@uk-erlangen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007109:Immunity; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000378:metabolism; D008807:Mice, Inbred BALB C; D058612:Nanodiamonds / Q000737:chemistry / Q000648:ultrastructure; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D058612:Nanodiamonds; D017382:Reactive Oxygen Species
keywords: NETosis; inflammation; nanoparticles; neutrophils; size