title: Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes.
abstract: Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-α or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-α induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes.
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA 02142.|Department of Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; and.
authors.forename: Marcelo O
authors.identifier: 0000-0003-4906-7698
authors.initials: MO
authors.lastname: Freire
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Jesmond
authors.identifier: 0000-0001-6328-3640
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Charles N
authors.identifier: 0000-0003-4627-8545
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA 02142; tvandyke@forsyth.org.|Department of Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; and.
authors.forename: Thomas E
authors.identifier: 0000-0003-0568-124X
authors.initials: TE
authors.lastname: Van Dyke
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D003579:Cytochrome Reductases / Q000276:immunology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010587:Phagocytosis / Q000276:immunology; D016133:Polymerase Chain Reaction; D018102:Receptors, Leukotriene B4 / Q000276:immunology / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D059467:Transcriptome
chemical_list: C513240:LTB4R protein, human; D018102:Receptors, Leukotriene B4; D015118:Eicosapentaenoic Acid; D003579:Cytochrome Reductases; C500897:GFER protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid