Positive Health Online

Abstract

FREIRE and COLLEAGUES, 1. Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA 02142; 2. Department of Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; 3. 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; 4. Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA 02142; tvandyke@forsyth.org .

Background

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.

Methodology

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.

Results

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.

Conclusion

These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes.

References

Freire MO1,2, Dalli J3, Serhan CN3, Van Dyke TE4,2.  Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes.  J Immunol.;198(2):718-728. doi: 10.4049/jimmunol.1601543. Epub 2016 Dec 19. 15 Jan 2017.