Estrogen receptors regulate innate immune cells and signaling pathways
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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