Estrogen receptors regulate innate immune cells and signaling pathways

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Abstract

Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ERs) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol most often promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells.

Section snippets

ER expression in immune cells

ER α and β proteins are members of the nuclear receptor super family encoded by the ESR1 and ESR2 genes, respectively [1]. Single ER chains form αα, ββ and αβ dimers, each of which is functionally distinct. As described below, ER-mediated mechanisms influence both the development and function of innate immune cells. Published studies document that ER mRNAs or proteins are expressed by hematopoietic progenitors and mature immune cells (see Table 1). Although ERs are regulated by transcriptional

ER signaling mechanisms

ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions. ERs form complexes at specific DNA sites with chromatin-modifying coregulators and other transcription factors, leading to epigenetic modifications of chromatin as well as transcription initiation [22]. The nuclear or “genomic” actions of ERs mediate many physiological effects of estrogens.

Studies of breast cancer cells have revealed mechanisms for the recruitment and action of ERs at specific sites

ERs regulate innate immune signaling pathways

ER activity has been shown to augment and dampen innate immune signaling pathways in dendritic cells and macrophages. An emerging theme is that ERα and physiological adult levels of estradiol promote the production of type I interferon (IFN). However, estradiol and ERs have been reported to exert either positive or negative regulatory effects on pro-inflammatory cytokine production; this varies with the cell type or estrogen dose. Pregnancy or higher doses of ectopic estrogens typically

Regulation of immune cell differentiation by estrogen receptors

As described below, ERα acts directly in HSCs, lymphoid progenitors and myeloid progenitors to promote developmental pathways. ER action in hematopoietic progenitors may have several consequences: (i) ERs may induce epigenetic changes in precursors that influence downstream developmental pathways or functional responses in mature cells. (ii) ERs may directly promote a developmental pathway by binding directly to a specific gene or genes within a pathway.

Multiple studies have shown that ER

Conclusion

A significant body of work now shows that estradiol and ER signaling regulate inflammatory pathways of innate immune cells, including dendritic cells and macrophages. Lower physiological levels of estradiol generally promote pathways leading to production of type I IFN, and often pro-inflammatory cytokines. However, in some cases ER signaling dampens these pathways even in lower estrogen environments. Higher physiological or supra-physiological levels of estrogens most often foster

Acknowledgment

S.K. was supported by NIH grants AI092511, AI083715 and HL119501.

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