Resolution Receptors in Inflammatory Chronic Disease

Objectives: Inflammation resolution is mediated by activation of G-protein coupled receptors that interact with lipid mediator agonists, including the lipoxins, resolvins and maresins. Type 2 diabetes (T2D) and periodontitis are both characterized by unresolved chronic inflammation. The aim of this study was to investigate the expression and function of receptors for the resolvin, RvE-1, which are BLT-1 and ERV-1 on neutrophils of subjects with uncontrolled Type 2 diabetes. In healthy myeloid cells, BLT-1 is the functional receptor on neutrophils and ERV-1 is the functional receptor on monocytes
Methods: Expression of BLT-1 and ERV-1 protein was evaluated by flow cytometry; mRNA expression was determined by q-PCR. Receptor function was determined by induction of intracellular signaling; phosphorylation of rS6 evaluated by immunofluorescence. Cells were stimulated in vitro with LPS (10ng/ml), TNF-α (10ng/ml), or both, with or without pre-treatment with RvE1 (10nM and 100nM).
Results: Healthy neutrophils express high levels of BLT-1 with minimal ERV1 expression. Neutrophils from T2D subjects expressed relatively less BLT-1 and more ERV-1. Baseline rS6 activation was significantly increased in neutrophils of T2D subjects; TNF-α and LPS ; induced rS6 phosphorylation in healthy and T2D and, as early as 15 minutes, the expression of the ERV-1 receptor was significantly increased (LPS, p<0.001; TNF-α p<0.01). Treatment of healthy neutrophils with RvE1 rescued altered expression of receptors and activation of rS6/AKT signaling through BLT-1. In patients with T2D, RvE1 treatment also rescued the neutrophil phenotype, but signaled primarily through ERV1.
Conclusions: The data suggest that the expression and function of neutrophil receptors for the resolvin RvE1 are markedly changed in T2D. In chronic T2D, elevation of systemic inflammation is reflected in pre-activation and hyper-responsiveness of neutrophils to stimulation. T2D neutrophils up-regulate ERV1 and down-regulate BLT-1 receptors and functionally change the response to agonists of resolution of inflammation.