GPER activation protects against epithelial barrier disruption by Staphylococcus aureus α-toxin.


FULLTEXT
Published:
02.06.2019
|
Last Revised:
05.15.2019
PMID:
30718654
Scientific reports
Journal Article

University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico School of Medicine, Department of Internal Medicine, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
University of New Mexico School of Medicine, Department of Cell Biology & Physiology, Albuquerque, NM, 87131, USA.
University of New Mexico School of Medicine, Department of Internal Medicine, Albuquerque, NM, 87131, USA.
University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA. phall@salud.unm.edu.

Abstract

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.

GrantID: P30 CA118100, Acronym: CA, Agency: NCI NIH HHS, Country: United States | GrantID: R01 CA163890, Acronym: CA, Agency: NCI NIH HHS, Country: United States | GrantID: UL1 TR001449, Acronym: TR, Agency: NCATS NIH HHS, Country: United States | GrantID: P20 GM121176, Acronym: GM, Agency: NIGMS NIH HHS, Country: United States | GrantID: CA163890, Agency: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI), Country: Array | GrantID: AI128159, Agency: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID), Country: Array | GrantID: R01 ES014639, Acronym: ES, Agency: NIEHS NIH HHS, Country: United States | GrantID: R01 CA194496, Acronym: CA, Agency: NCI NIH HHS, Country: United States | GrantID: KL2 TR001448, Acronym: TR, Agency: NCATS NIH HHS, Country: United States | GrantID: R21 AI128159, Acronym: AI, Agency: NIAID NIH HHS, Country: United States | GrantID: CA194496, Agency: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI), Country: Array | GrantID: ES014639, Agency: U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS), Country: Array