| Autor: |
Triplett KD; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Pokhrel S; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Castleman MJ; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Daly SM; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Elmore BO; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Joyner JA; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Sharma G; University of New Mexico School of Medicine, Department of Internal Medicine, Albuquerque, NM, 87131, USA., Herbert G; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Campen MJ; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA., Hathaway HJ; University of New Mexico School of Medicine, Department of Cell Biology & Physiology, Albuquerque, NM, 87131, USA., Prossnitz ER; University of New Mexico School of Medicine, Department of Internal Medicine, Albuquerque, NM, 87131, USA., Hall PR; University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA. phall@salud.unm.edu. |
| Abstrakt: |
Sex bias in innate defense against Staphylococcus aureus skin and soft tissue infection (SSTI) is dependent on both estrogen production by the host and S. aureus secretion of the virulence factor, α-hemolysin (Hla). The impact of estrogen signaling on the immune system is most often studied in terms of the nuclear estrogen receptors ERα and ERβ. However, the potential contribution of the G protein-coupled estrogen receptor (GPER) to innate defense against infectious disease, particularly with respect to skin infection, has not been addressed. Using a murine model of SSTI, we found that GPER activation with the highly selective agonist G-1 limits S. aureus SSTI and Hla-mediated pathogenesis, effects that were absent in GPER knockout mice. Specifically, G-1 reduced Hla-mediated skin lesion formation and pro-inflammatory cytokine production, while increasing bacterial clearance. In vitro, G-1 reduced surface expression of the Hla receptor, ADAM10, in a human keratinocyte cell line and increased resistance to Hla-mediated permeability barrier disruption. This novel role for GPER activation in skin innate defense against infectious disease suggests that G-1 may have clinical utility in patients with epithelial permeability barrier dysfunction or who are otherwise at increased risk of S. aureus infection, including those with atopic dermatitis or cancer. |
