Prostaglandin E2 threshold dictates susceptibility to skin infection in diabetic mice

Abstract

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is the primary cause of skin infection in people with diabetes. MRSA skin infection is characterized by the migration of phagocytes and abscess formation to prevent deeper tissue infections. However, the events that drive poor host defense in diabetes is poorly understood. Here, we examined the role of the lipid mediator prostaglandin E2 (PGE2) and its impact on host defense during MRSA skin infection in diabetes. We have shown that diabetic mice are unable to control MRSA skin infection, along with excessive cytokine production and neutrophil migration. Our data indicate that PGE2 production is lower in diabetic mice than nondiabetic mice at both days 1 and 9. Daily topical treatment with a PGE2 analog decreased lesion size and improved bacterial clearance in the skin of infected diabetic mice. Reduced lesion size in PGE2-treated diabetic mice correlated with decreased production of the cytokines TNF-, IL-1, and IL-6 and neutrophil migration. While we did observe a well-defined abscess in infected nondiabetic mice, infection in diabetic mice resulted in poor abscess formation; and topical PGE2 treatment restores abscess formation. Poor skin defense in diabetic mice also correlated with increased numbers of dead cells at days 1 and 9 post-infection suggesting that dead cells are not eliminated. When we studied the expression of molecules involved in dead cell ingestion, we observed an increased abundance of inhibitory receptor SIRPa in infected diabetic mice and PGE2 ointment restored SIRPa levels back to those observed in infected nondiabetic mice. These data indicate that the threshold of PGE2 drives the inflammatory milieu during infection and effects skin homeostasis in diabetes.