title: Ménage-à-Trois: The Ratio of Bicarbonate to CO2and the pH Regulate the Capacity of Neutrophils to Form NETs.
abstract: In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing capacity of phorbol esters (phorbol-2-myristate-13-acetate), ionomycin, monosodium urate, and LPS. In contrast, an acidic environment impaired NET formation both spontaneous and induced. Our findings indicate that intracellular alkalinization of neutrophils in response to an alkaline environment leads to an increase of intracellular calcium and neutrophil activation. We further found that the anion channel blocker DIDS strongly reduced NET formation induced by bicarbonate. This finding suggests that the effects observed are due to a molecular program that renders neutrophils susceptible to NET formation. Inflammatory foci may be characterized by an acidic environment. Our data indicate that NET formation is favored by the higher pH at the border regions of inflamed areas. Moreover, our findings highlight the necessity for strict pH control during assays of NET formation.
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , 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-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Aparna
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Paulus
authors.affiliation: Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gößwein
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , 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-University Erlangen-Nürnberg (FAU) , 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-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Mona H
authors.initials: MH
authors.lastname: Biermann
authors.affiliation: Optical Imaging Center Erlangen (OICE), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.affiliation: ENT Clinic, Section of Experimental Oncology and Nanomedicine (SEON), University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Friedrich
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Munoz
authors.affiliation: Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Georg Andreas
authors.initials: GA
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Leppkes
keywords: CO2; NET; bicarbonate; calcium; inflammation; neutrophil extracellular traps; neutrophils; pH