Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice.
People with diabetes are more prone to Staphylococcus aureus skin infection than healthy individuals. Control of S. aureus infection depends on dendritic cell (DC)-induced T-helper 17 (Th17)-mediated neutrophil recruitment and bacterial clearance. DC ingestion of infected apoptotic cells (IACs) drive prostaglandin E2(PGE2) secretion to generate Th17 cells. We speculated that hyperglycemia inhibits skin DC migration to the lymph nodes and impairs the Th17 differentiation that accounts for poor skin host defense in diabetic mice. Diabetic mice showed increased skin lesion size and bacterial load and decreased PGE2secretion and Th17 cells compared with nondiabetic mice after methicillin-resistant S. aureus (MRSA) infection. Bone marrow-derived DCs (BMDCs) cultured in high glucose (25 mmol/L) exhibited decreased Ptges mRNA expression, PGE2production, lower CCR7-dependent DC migration, and diminished maturation after recognition of MRSA-IACs than BMDCs cultured in low glucose (5 mmol/L). 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 DC 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.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.|University of São Paulo, Ribeirão Preto, Brazil.|Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Júlio de Mesquita Filho," Araraquara, Brazil.
Naiara N
NN
Dejani
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
Stephanie L
SL
Brandt
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.|University of São Paulo, Ribeirão Preto, Brazil.
Annie
A
Piñeros
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
Nicole L
NL
Glosson-Byers
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
Sue
S
Wang
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
Young Min
YM
Son
University of São Paulo, Ribeirão Preto, Brazil.|Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Júlio de Mesquita Filho," Araraquara, Brazil.
Alexandra I
AI
Medeiros
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN h.serezan@vanderbilt.edu.
C Henrique
CH
Serezani
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D011459:Prostaglandins E, Synthetic / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000382:microbiology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism*
D011459:Prostaglandins E, Synthetic