PGE2 imbalance in diabetic mice impairs dendritic cell maturation and favors methicillin-resistant S. aureus skin infection

Abstract

Abstract Diabetics are more prone to Staphylococcus aureus skin infection than healthy individuals. Neutrophil recruitment and apoptosis are hallmarks of S. aureus infections. Ingestion of infected apoptotic cells (IAC) by dendritic cells (DC) lead to secretion of Th17-related cytokines and prostaglandin E2 (PGE2). We speculate that hyperglycemia inhibits DC migration to the lymph nodes, in a manner dependent on PGE2 levels and impairs Th17 differentiation during MRSA skin infection in type 1 diabetic mice (T1D). Control and T1D mice were subcutaneously (s.c.) infected with 5×106 MRSA CFU. T1D mice showed increased lesion and bacterial load and decreased Th17 population in the skin than nondiabetic mice. We next determined if decreased Th17 correlates with deficient DC migration to draining LN. To track DC migration, mice received s.c. FarRed to stain the skin cells. Our results show that T1D had lower percentage and number of FarRed+DCs+ in the LN than controls.. Impaired DC migration and Th17 differentiation in T1D correlated with decreased skin PGE2 levels. When BMDCs were cultured in high glucose, we observed decreased PGE2 production, migration and maturation after recognition of MRSA-IAC when compared to BMDC kept in normal glucose. Topical treatment with PGE analog (Misoprostol), restored skin DC migration, Th17 differentiation, increased anti-microbial peptides, decreased CFU loads and lesion size in T1D. These data suggest that PGE2 imbalance in hyperglycemia impairs DC migration to LN and fail to mount Th17 responses leading to increased lesions and delayed healing in MRSA skin infections. Misoprostol may be a promising candidate to improve innate and adaptive immune responses in diabetic skin infections.