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.
References (85)
- et al.
Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations
Immunol. Lett.
(2005) - et al.
Estrogen inhibits dendritic cell maturation to RNA viruses
Blood
(2008) - et al.
The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor alpha signaling
Blood
(2012) - et al.
Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway
Cell. Immunol.
(2001) - et al.
Estrogen receptor-alpha gene expression in the cortex: sex differences during development and in adulthood
Horm. Behav.
(2011) - et al.
Auto-regulation of the estrogen receptor promoter
J. Steroid Biochem. Mol. Biol.
(1997) - et al.
Chromatin and epigenetic determinants of estrogen receptor alpha (ESR1) signaling
Mol. Cell. Endocrinol.
(2014) - et al.
Estrogen receptor-mediated long-range chromatin interactions and transcription in breast cancer
Mol. Cell. Endocrinol.
(2014) - et al.
Regulation of specific target genes and biological responses by estrogen receptor subtype agonists
Curr. Opin. Pharmacol.
(2010) - et al.
Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression
Mol. Cell
(2006)
Emerging evidence of the importance of rapid, non-nuclear estrogen receptor signaling in the cardiovascular system
Steroids
Down-regulation of endothelial cell estrogen receptor expression by the inflammation promoter LPS
Mol. Cell. Endocrinol.
Estrogen modulation of endosome-associated toll-like receptor 8: an IFNalpha-independent mechanism of sex-bias in systemic lupus erythematosus
Clin. Immunol.
Estrogen receptor alpha modulates Toll-like receptor signaling in murine lupus
Clin. Immunol.
Transcription factor cross-talk: the estrogen receptor and NF-kappaB
Trends Endocrinol. Metab.
Hematopoietic stem cell heterogeneity takes center stage
Cell Stem Cell
Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients
Blood
Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors
Blood
Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4
Blood
Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells
Blood
Estrogen receptors regulate an inflammatory pathway of dendritic cell differentiation: mechanisms and implications for immunity
Horm. Behav.
Estrogen receptors: how do they signal and what are their targets
Physiol. Rev.
X-chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-alpha production of plasmacytoid dendritic cells from women
J. Immunol.
Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes
J. Immunol.
Estrogen alters thresholds for B cell apoptosis and activation
J. Clin. Invest.
Estrogen receptor-alpha deficiency promotes increased TNF-alpha secretion and bacterial killing by murine macrophages in response to microbial stimuli in vitro
J. Leukoc. Biol.
Estrogen receptor alpha signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis
J. Immunol.
Estrogen preferentially promotes the differentiation of CD11c+ CD11b(intermediate) dendritic cells from bone marrow precursors
J. Immunol.
Estrogen selectively promotes the differentiation of dendritic cells with characteristics of Langerhans cells
J. Immunol.
Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development
Proc. Natl. Acad. Sci. U.S.A.
Estrogen receptor-beta ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease
Eur. J. Immunol.
Estrogen receptor beta expression in the mouse forebrain: age and sex differences
J. Comp. Neurol.
Age and stage dependency of estrogen receptor expression by lymphocyte precursors
Proc. Natl. Acad. Sci. U.S.A.
Estradiol acts directly on bone marrow myeloid progenitors to differentially regulate GM-CSF or Flt3 ligand-mediated dendritic cell differentiation
J. Immunol.
Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy
Nature
Estradiol regulates expression of estrogen receptor ERalpha46 in human macrophages
PLoS ONE
Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy
Cancers (Basel)
Genomic targets of nuclear estrogen receptors
Mol. Endocrinol.
Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action
Mol. Endocrinol.
Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions
Proc. Natl. Acad. Sci. U.S.A.
Palmitoylation regulates 17beta-estradiol-induced estrogen receptor-alpha degradation and transcriptional activity
Mol. Endocrinol.
Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor alpha
J. Immunol.
Cited by (673)
Therapeutic implications of the interplay between interferons and ER in breast cancer
2024, Cytokine and Growth Factor ReviewsSex Matters: From Bile Acid Metabolism to Liver Cancer
2024, Cellular and Molecular Gastroenterology and HepatologyInsights into estrogen impact in oral health & microbiome in COVID-19
2024, BMC MicrobiologyCandidate Blood MicroRNAs as Potential Biomarkers in Patients with Active and Latent Pulmonary Tuberculosis Infection
2024, Journal of Pure and Applied Microbiology