Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes

J Immunol. 2017 Jan 15;198(2):718-728. doi: 10.4049/jimmunol.1601543. Epub 2016 Dec 19.

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.

MeSH terms

  • Adult
  • Cells, Cultured
  • Chromatography, Liquid
  • Cytochrome Reductases / immunology
  • Cytochrome Reductases / metabolism*
  • Diabetes Mellitus, Type 2 / immunology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Eicosapentaenoic Acid / analogs & derivatives*
  • Eicosapentaenoic Acid / immunology
  • Eicosapentaenoic Acid / metabolism
  • Female
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Male
  • Middle Aged
  • Neutrophils / immunology
  • Neutrophils / metabolism*
  • Phagocytosis / immunology
  • Polymerase Chain Reaction
  • Receptors, Leukotriene B4 / immunology
  • Receptors, Leukotriene B4 / metabolism*
  • Tandem Mass Spectrometry
  • Transcriptome

Substances

  • LTB4R protein, human
  • Receptors, Leukotriene B4
  • Eicosapentaenoic Acid
  • Cytochrome Reductases
  • GFER protein, human
  • 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid