title: A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels.
abstract: In phagocytes, pathogen recognition is followed by Ca(2+) mobilization and NADPH oxidase 2 (NOX2)-mediated "oxidative burst," which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca(2+) channels control store-operated Ca(2+) entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit. Staphylococcal infection of mice reduced the expression of the gene encoding the redox-sensitive Orai1 and increased the expression of the gene encoding the redox-insensitive Orai3 in the lungs or in bronchoalveolar lavages. A similar switch from ORAI1 to ORAI3 occurred in primary human monocytes exposed to bacterial peptides in culture. These alterations in ORAI1 and ORAI3 abundance shifted the channel assembly toward a more redox-insensitive configuration. Accordingly, silencing ORAI3 increased the redox sensitivity of the channel and enhanced oxidation-induced inhibition of NOX2. We generated a mathematical model that predicted additional features of the Ca(2+)-redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses.
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Saul
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Gibhardt
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany. Department of Theoretical Physics, Saarland University, Saarbrücken 66123, Germany. Molecular Biophysics, CIPMM, School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Lis
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Pasieka
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Conrad
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg 66421, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jung
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg 66421, Germany.
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Gaupp
authors.affiliation: Department of Anatomy, School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Wonnenberg
authors.affiliation: Department of Anatomy, School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Ebru
authors.initials: E
authors.lastname: Diler
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Hospital of Saarland, Homburg 66421, Germany.
authors.forename: Hedwig
authors.initials: H
authors.lastname: Stanisz
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Hospital of Saarland, Homburg 66421, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Schwarz
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg 66421, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg 66421, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Anatomy, School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kappl
authors.affiliation: Department of Theoretical Physics, Saarland University, Saarbrücken 66123, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Rieger
authors.affiliation: Molecular Biophysics, CIPMM, School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Niemeyer
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPPM), School of Medicine, Saarland University, Homburg 66421, Germany. ivan.bogeski@uks.eu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
mesh_terms: D000818:Animals; D002118:Calcium / Q000276:immunology* / Q000378:metabolism; D000071739:Calcium Release Activated Calcium Channels / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D011023:Pneumonia, Staphylococcal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology* / Q000378:metabolism
chemical_list: D000071739:Calcium Release Activated Calcium Channels; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002118:Calcium