title: Prolonged exposure to neutrophil extracellular traps can induce mitochondrial damage in macrophages and dendritic cells.
abstract: Neutrophils are one the earliest, crucial innate defenses against innumerable pathogens. Their main microbicidal activities include phagocytosis and degranulation, with many pharmacologically active molecules contributing to inflammation. Recently, a novel antimicrobial mechanism was discovered; the Neutrophil Extracelullar Traps (NETs) formed by extrusion of DNA and associated molecules (histones, elastase, antimicrobial peptides, among others) which trap and kill microorganisms. Since NETs were recently described, research has focused on their induction and microbicidal properties, and recently on disease involvement. However, the functional consequences of NETs interacting with other immune cells, either resident or recruited during early inflammation, have not been assessed. We therefore investigated the consequences of exposing two major APCs, macrophages (Mfs) and conventional Dendritic Cells (cDCs) to NETs. Our data revealed that at early times (30 min), both Antigen Presenting Cells (APCs) showed induction of important costimulatory molecules (CD80, CD86). Unexpectedly, however, at later times (6 and 24 hours) NETs apparently triggered a cell death process in these APCs by a caspase- and Apoptosis induced factor (AIF)-dependent pathway, suggesting mitochondrial damage. By rhodamine-123 labelling we found that in both APCs, relatively prolonged exposure to NETs or their components importantly decreased the mitochondrial membrane potential. Ultrastructural analysis confirmed mitochondrial alterations in both APCs. Our results would suggest that early in inflammation, NETs can activate the two main APCs (Mfs and cDCs), but as the process continues, NETs can then initiate apoptosis of these cells through mitochondrial harm. Conceivable, this "late" induction of cell death in these two APCs might start limiting an ongoing inflammatory process to control it.
authors.affiliation: Department of Cell Biology, Cinvestav-IPN. AV. IPN No 2508, Zacatenco, C.P. 07330 D.F México.
authors.forename: Luis
authors.initials: L
authors.lastname: Donis-Maturano
authors.affiliation: Department of Immunology, ENCB-IPN, Col. Santo Tomas, C.P. 11340 D.F Mexico.
authors.forename: Luvia E
authors.initials: LE
authors.lastname: Sánchez-Torres
authors.affiliation: Department of Cell Biology, INPer., Montes Urales 800, Lomas Virreyes, C.P.11000 D.F México.
authors.forename: Arturo
authors.initials: A
authors.lastname: Cerbulo-Vázquez
authors.affiliation: Department of Immunology, ENCB-IPN, Col. Santo Tomas, C.P. 11340 D.F Mexico.
authors.forename: Rommel
authors.initials: R
authors.lastname: Chacón-Salinas
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Gina S
authors.initials: GS
authors.lastname: García-Romo
authors.affiliation: Department of Cell Biology, Cinvestav-IPN. AV. IPN No 2508, Zacatenco, C.P. 07330 D.F México.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Orozco-Uribe
authors.affiliation: Department of Cell Biology, Cinvestav-IPN. AV. IPN No 2508, Zacatenco, C.P. 07330 D.F México.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Yam-Puc
authors.affiliation: Department of Cell Biology, INPer., Montes Urales 800, Lomas Virreyes, C.P.11000 D.F México.
authors.forename: Marco A
authors.initials: MA
authors.lastname: González-Jiménez
authors.affiliation: Department of Cell Biology, INPer., Montes Urales 800, Lomas Virreyes, C.P.11000 D.F México.
authors.forename: Yuriria L
authors.initials: YL
authors.lastname: Paredes-Vivas
authors.affiliation: Department of Cell Biology, Cinvestav-IPN. AV. IPN No 2508, Zacatenco, C.P. 07330 D.F México.
authors.forename: Juana
authors.initials: J
authors.lastname: Calderón-Amador
authors.affiliation: Department of Immunology, ENCB-IPN, Col. Santo Tomas, C.P. 11340 D.F Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Estrada-Parra
authors.affiliation: Department of Immunology, ENCB-IPN, Col. Santo Tomas, C.P. 11340 D.F Mexico.
authors.forename: Iris
authors.initials: I
authors.lastname: Estrada-García
authors.affiliation: Department of Cell Biology, Cinvestav-IPN. AV. IPN No 2508, Zacatenco, C.P. 07330 D.F México.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Flores-Romo
keywords: Dendritic cells; Macrophages; Mitochondrial damage; NETs