title: Hydrogen Peroxide Triggers a Dual Signaling Axis To Selectively Suppress Activated Human T Lymphocyte Migration.
abstract: H2O2is an early danger cue required for innate immune cell recruitment to wounds. To date, little is known about whether H2O2is required for the migration of human adaptive immune cells to sites of inflammation. However, oxidative stress is known to impair T cell activity, induce actin stiffness, and inhibit cell polarization. In this study, we show that low oxidative concentrations of H2O2also impede chemokinesis and chemotaxis of previously activated human T cells to CXCL11, but not CXCL10 or CXCL12. We show that this deficiency in migration is due to a reduction in inflammatory chemokine receptor CXCR3 surface expression and cellular activation of lipid phosphatase SHIP-1. We demonstrate that H2O2acts through an Src kinase to activate a negative regulator of PI3K signaling, SHIP-1 via phosphorylation, providing a molecular mechanism for H2O2-induced chemotaxis deficiency. We hypothesize that although H2O2serves as an early recruitment trigger for innate immune cells, it appears to operate as an inhibitor of T lymphocyte immune adaptive responses that are not required until later in the repair process.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom; and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Ball
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Biomedical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Isabella
authors.initials: I
authors.lastname: Vlisidou
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom; and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Blunt
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Biomedical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Will
authors.initials: W
authors.lastname: Wood
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom; and S.G.Ward@bath.ac.uk.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ward
mesh_terms: D000199:Actins / Q000378:metabolism; D056704:Adaptive Immunity; D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054371:Chemokine CXCL11 / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D055815:Young Adult; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D054371:Chemokine CXCL11; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D054367:Receptors, CXCR3; D019061:src-Family Kinases; C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; C000606430:INPP5D protein, human