G Protein-Coupled Estrogen Receptor 1 Regulates Human Neutrophil Functions

Abstract

Background: The role of estrogens in immune functioning is relatively well known under both physiological and pathological conditions. Neutrophils are the most abundant circulating leukocytes in humans, and their abundance and function are regulated by estrogens, since they express estrogen receptors (ERs). Traditionally, estrogens were thought to act via classical nuclear ERs, namely ERα and ERβ. However, it was observed that some estrogens induced biological effects only minutes after their application. This rapid, “nongenomic” effect of estrogens is mediated by a membrane-anchored receptor called G protein-coupled estrogen receptor 1 (GPER1). Nevertheless, the expression and role of GPER1 in the immune system has not been exhaustively studied, and its relevance in neutrophil functions remains unknown. Methods: Human neutrophils were incubated in vitro with 10-100 µ<smlcap>M</smlcap> of the GPER1-specific agonist G1 alone or in combination with lipopolysaccharide. GPER1 expression and subcellular localization, respiratory burst, life span, gene expression profile, and cell signaling pathways involved were then analyzed in stimulated neutrophils. Results: Human neutrophils express a functional GPER1 which regulates their functions through cAMP/protein kinase A/cAMP response element-binding protein, p38 mitogen-activated protein kinase, and extracellular regulated MAPK signaling pathways. Thus, GPER1 activation in vitro increases the respiratory burst of neutrophils, extends their life span, and drastically alters their gene expression profile. Conclusions: Our results demonstrate that GPER1 activation promotes the polarization of human neutrophils towards a proinflammatory phenotype and point to GPER1 as a potential therapeutic target in immune diseases where neutrophils play a key role.

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

“…GPER activation has a variety of effects on innate immune function, including modulation of macrophage cytokine production and neutrophil function 30–32 , as well as reversing stroke-induced immunosuppression 33 . To determine whether GPER activation would support innate immune defense against infectious disease, we evaluated the effects of GPER activation on the outcomes of S. aureus infection using a well characterized murine model of SSTI 9 .…”

“…More recently, the G protein-coupled estrogen receptor (GPER) has been recognized as mediating many of the rapid and even long-term effects of estrogen 28,29 . GPER activation has been shown to modulate macrophage cytokine production and neutrophil function 30–32 , as well as to reverse stroke-induced peripheral immunosuppression in ovariectomized mice 33 . Interestingly, GPER activation by the highly selective GPER agonist G-1 34 has also been reported to block disruption of endothelial barrier integrity as shown by its ability to limit blood-brain barrier (BBB) disruption following global cerebral ischemia (GCI) 35 .…”

Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers

“…Likewise, G-1 promoted the expression of IL1B, CXCL2, COX2, SOCS3, GCSF, and IL1RA genes and increased the production of CXCL8 protein. These effects occurred through the cAMP/PKA/CREB, p38 MAPK, and ERK signaling pathways (98). G-1 magnified the effect of eotaxin on eosinophil chemotaxis and inhibited spontaneous apoptosis of eosinophils by reducing caspase-3 activity, but it had the opposite effect on eosinophils previously stimulated with IL-5, a cytokine that promotes their survival in eosinophilic inflammation, inducing apoptosis by increasing caspase-3 activity.…”

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

“…Previous reports have shown that polymorphonuclear cells express the classical ERα and ERβ estrogen receptors, which were believed to have mostly anti-inflammatory actions ( 45 , 46 ). Contrary to these reports regarding the effects of estrogen on neutrophils, G1 activation of GPER1 triggered a proinflammatory reaction with increased cytokine (IL1b, CXCL8) and COX2 expression, enhanced respiratory burst and increased life span ( 36 ). This finding supports a differential role of GPER1, compared to classical estrogen receptors, in regulating inflammation in these cells.…”

“…In the few studies that included intracellular signaling, the major GPER1-related pathways involved extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K), and NFκB ( 26 , 29 , 32 ). In human neutrophils, the major pathways also involved cAMP/protein kinase A/cAMP-response element-binding protein, p38 mitogen-activated protein kinase, and ERK ( 36 ).…”