Estrogen Receptor Signaling in the Immune System

Abstract

The immune system functions in a sexually dimorphic manner with females exhibiting more robust immune responses than males. However, how female sex hormones affect immune function in normal homeostasis and in autoimmunity is poorly understood. In this review we discuss how estrogens affect innate and adaptive immune cell activity and how dysregulation of estrogen signaling underlies the pathobiology of some autoimmune diseases and cancers. The potential roles of the major circulating estrogens, and each of the three estrogen receptors (ERα, ERβ and GPER) in the regulation of the activity of different immune cells are considered. This provides the framework for a discussion of the impact of ER modulators (aromatase inhibitors, Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Downregulators (SERDs)) on immunity. Synthesis of this information is timely given the considerable interest of late in defining the mechanistic basis of gender biased responses/outcomes in patients with different cancers treated with immune checkpoint blockade. It will also be instructive with respect to the further development of ER modulators that modulate immunity in a therapeutically useful manner.

Gender-Specific Impact of Sex Hormones on the Immune System

“…Neutrophils, alongside their hematopoietic progenitor cells, express ARs and androgens exert a stimulatory role with regards to their differentiation [ 16 ], granulopoiesis, and cytokine production [ 13 , 21 ]. Both ERs and PRs are also expressed in neutrophils and contribute to regulate neutrophilic functions [ 17 , 22 ]. In women, the spontaneous apoptosis of the neutrophils is markedly delayed compared to men, and the administration of estradiol (E 2 ) and progesterone (P 4 ) further increases the lifespan of neutrophils in males and females ( Table 1 ) [ 23 ].…”

“…Estrogen receptors (ERs) regulate both the innate and adaptive immune pathways in response to circulating estrogen levels. Each of the three ERs (ERα, ERβ, and the G protein-coupled receptor) play a role in immune cell development, differentiation, and function [ 17 ], besides regulating the main physiological processes in the reproductive, endocrine, nervous, skeletal, and cardiovascular systems in both women and men [ 18 ].…”

Tailoring therapies to counter the divergent immune landscapes of breast cancer

“…However, 70% of breast cancer diagnoses are ER/PR+ (collectively referred to as hormone receptor positive, HR+), thus understanding the TIME of these tumors is of clinical importance (Goldberg et al, 2021). While endocrine therapy is usually restricted to HR+ breast cancer, the ER is expressed in other cell types, including immune cells (Chakraborty et al, 2023). Moreover, in premenopausal women, significant levels of estrogen may reach the mammary gland and reshape the TIME (Svoronos et al, 2017).…”

Lipid metabolism in type 1 diabetes mellitus: Pathogenetic and therapeutic implications

“…The functionality of the immune system exhibits a remarkable sexual dimorphism. Generally, females manifest more robust immune response than males ( 110 ). Estrogens elicit huge impact on regulating innate immunity and adaptive immunity in the normal immune system and in different diseases such as tumor and autoimmune disease.…”

“…Additionally, compelling evidence demonstrates that estrogens can promote Treg differentiation and increase the immunosuppressive activities in order to restore immune tolerance. Low levels of E2 enhance Th1 response while elevated E2 favor a Th2 response ( 110 ). However, beneficial effects of estrogen regulating other immune cells have not yet been demonstrated in humans as well as in NOD mice.…”