Resolution of Inflammation in Type 2 Diabetes

Abstract

Unresolved inflammation is a key factor linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized pro-resolving lipid mediators, such as resolvin E1 (RvE1), and activation of cognate g-protein coupled receptors (GPCR). RvE1 binds to BLT-1 on neutrophils and ERV-1/ChemR23 on monocyte/macrophages. The mechanism by which innate immune cells in metabolic diseases fail to respond to endogenous pro-resolution signals is not well understood. The goal of the studies presented was to investigate the expression and function of ERV-1 receptor on neutrophils from type 2 diabetes subjects. Results demonstrate that neutrophils from type 2 diabetic subjects expressed significantly increased ERV-1 receptor on their cell surface that was functional, as determined by phosphorylation of the signalling protein, ribosomal S6 (rS6). Healthy neutrophils express functional BLT-1 and low levels of minimally functional ERV-1. Stimulation with TNFα or LPS increased expression of ERV1 on neutrophils of both healthy and diabetic subjects. Increased expression of ERV1 was reversed by pre- and post- treatment with RvE1. TNFα or LPS stimulation increased phospho-rS6 significantly more in type 2 diabetic neutrophils than healthy subjects. Receptor antagonism experiments revealed that the phospho-rS6 increase was mediated by BLT-1 in healthy subject neutrophils and ERV1 in diabetic subject neutrophils. Diabetic neutrophil ERV-1 over expression was reversed by RvE1 treatment in a dose response manner (1-10nM). Analysis of the bioactive lipid metabolome revealed higher expression of inflammatory mediators in type 2 diabetes serum than healthy control with slightly reduced levels of RvE1 in type 2 diabetics (by ELISA). Neutrophil phagocytosis of pathogenic bacteria and inert bioparticles was impaired in type 2 diabetes. RvE1, signalling through ERV-1 but not BLT-1, partially rescued deficient phagocytosis by type 2 diabetic neutrophils with a clear shift of the dose response requiring increased RvE1. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils is significantly higher than healthy controls. Overall the findings in this dissertation further our understanding of the importance of expression and function of key resolution receptors in health versus disease and dysregulation of inflammation in type 2 diabetes.