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.
Sci Rep. 2019 Feb 4;9(1):1343. doi: 10.1038/s41598-018-37951-3.
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.
性别偏见与金黄色葡萄球菌皮肤和软组织感染（SSTI）的先天防御有关，这取决于宿主产生的雌激素和金黄色葡萄球菌分泌的毒力因子α-溶血素（Hla）。雌激素信号对免疫系统的影响通常是通过核雌激素受体 ERα 和 ERβ 来研究的。然而，G 蛋白偶联雌激素受体（GPER）对先天防御感染性疾病，特别是皮肤感染的潜在贡献尚未得到解决。使用金黄色葡萄球菌 SSTI 的小鼠模型，我们发现，高选择性激动剂 G-1 激活 GPER 可限制金黄色葡萄球菌 SSTI 和 Hla 介导的发病机制，而在 GPER 敲除小鼠中则没有这些作用。具体而言，G-1 减少了 Hla 介导的皮肤损伤形成和促炎细胞因子的产生，同时增加了细菌清除率。在体外，G-1 减少了人类角质形成细胞系中 Hla 受体 ADAM10 的表面表达，并增加了对 Hla 介导的通透性屏障破坏的抵抗力。GPER 激活在皮肤先天防御感染性疾病中的这种新作用表明，G-1 可能对上皮通透性屏障功能障碍或其他金黄色葡萄球菌感染风险增加的患者具有临床应用价值，包括特应性皮炎或癌症患者。
