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

Abstract

G protein-coupled estrogen receptor 1 (GPER1), is a functional estrogen receptor involved in estrogen related actions on several systems including processes of the nervous, reproductive, metabolic, cardiovascular, and immune system. Regarding the latter, GPER is expressed in peripheral B and T lymphocytes as well as in monocytes, eosinophils, and neutrophils. Several studies have implicated GPER in immune-mediated diseases like multiple sclerosis, Parkinson’s disease, and atherosclerosis-related inflammation, while a recent report suggests that its deletion could be responsible for a form of familial immunodeficiency. It has also been suggested that it is a key regulator of immune-mediated events in breast, pancreatic, prostate, and hepatocellular cancer as well as in melanoma. GPER has been also reported to interact with classic ER-alpha or its splice variants in order to modify immune functions. This review aims to present current knowledge relating GPER to immune functions, the cellular and signaling pathways involved, as well as the potential clinical implications of GPER modulation in immune-related diseases.

G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

“…For example, tumor-associated macrophages contribute to tumor progression and metastasis by secreting multiple growth factors and inflammatory cytokines into the tumor microenvironment [ 112 , 113 ]. Estrogens display multiple effects on the immune system, including both development and function [ 114 , 115 , 116 ]. ERα, ERβ, and GPER knockout (KO) mouse studies revealed that ERα mediates an early developmental blockage of thymocytes, whereas GPER is required for apoptosis of T cell double-positive thymocytes [ 117 ].…”

G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Mantle Cell Lymphoma Growth in Preclinical Models

“…It was shown that G-1 suppressed proliferation in several types of cancer cell lines by inhibiting NF-κB phosphorylation and cross-talk between GPER signaling and NF-κB signaling has been noted. For example, GPER activation reduces the secretion of inflammatory factors, such as IL-6 and TNF-α from monocyte/macrophages in mice, suggesting that GPER indirectly regulates NF-κB and reduces inflammation ( 42 , 43 ). In human, GPER activation alleviates inflammation by interacting directly with the ER-α splice variant and the p65 subunit of NF-κB in primary monocytes ( 42 ).…”

“…These data suggest that GPER plays diverse functions depending on cell types, underlying pathology, and tumor micro-environment. GPER is expressed in the early stages of immune cells including B cells ( 43 ). But related functional studies are very limited.…”

Role of G Protein-Coupled Estrogen Receptor in Digestive System Carcinomas: A Minireview

“…In the immune system, GPER is expressed in each population of immune cells, including peripheral B and T lymphocytes, monocytes, eosinophils, and neutrophils. 65 In addition, it regulates estrogenic effects on immune functions in humans and other species. 66 , 67 The immunomodulatory effect of GPER has also been beneficial in immune-mediated diseases such as multiple sclerosis, liver fibrosis, and autoimmune encephalomyelitis by reducing the levels of inflammatory cytokines and upregulating programmed death-1 (PD-1) on CD4 + Foxp3 + regulatory T cells.…”