Diabetics are more prone to Staphylococcus aureus skin infection than healthy individuals. Control of S. aureus infection is dependent on dendritic cell (DC)-induced Th17-mediated neutrophil recruitment and bacterial clearance. DC ingestion of infected apoptotic cells (IAC) drive prostaglandin E2 (PGE2) secretion to generate Th17 cells. We speculated that hyperglycemia inhibits skin DC migration to the lymph nodes (LNs) and impairs Th17 differentiation that accounts for poor skin host defense in diabetic mice. Diabetic mice show increased skin lesion size, bacterial load, decreased PGE2 and Th17 cells compared to nondiabetic mice after Methicillin-resistant S. aureus (MRSA) infection. Bone marrow-derived DCs (BMDCs) cultured in high glucose (25 mM) exhibits decreased 3Ptges mRNA expression, PGE2 production, lower CCR7-dependent DC migration, and diminished maturation after recognition of MRSA-IAC than BMDCs cultured in low glucose (5 mM). Similar events were observed in DCs from diabetic mice infected with MRSA. Topical treatment of diabetic mice with the PGE analog Misoprostol improved host defense against MRSA skin infection by restoring dendritic cell migration to draining lymph nodes, Th17 differentiation, and increased antimicrobial peptide expression. These findings identify a novel mechanism involved in poor skin host defense in diabetes and propose a targeted strategy to restore skin host defense in diabetes.
- Received May 6, 2016.
- Accepted August 28, 2016.
- © 2016 by the American Diabetes Association.