Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

Abstract

17β-Estradiol (E2) has been shown to regulate GM-CSF– or Flt3 ligand–driven dendritic cell (DC) development through estrogen receptor (ER) α signaling in myeloid progenitors. ERα regulates transcription of target genes through two distinct activation functions (AFs), AF-1 and AF-2, whose respective involvement varies in a cell type– or tissue-specific manner. In this study, we investigated the role of ERα AFs in the development and effector functions of inflammatory DCs, steady-state conventional DCs, and plasmacytoid DCs (pDC), using mouse lacking either AF-1 or AF-2. In agreement with previous works, we showed that E2 fostered the differentiation and effector functions of inflammatory DCs through ERα-dependent upregulation of IFN regulatory factor (IRF)-4 in GM-CSF–stimulated myeloid progenitors. Interestingly, whereas AF-1 was required for early IRF-4 upregulation in DC precursors, it was dispensable to enhance IRF-4 expression in differentiated DCs to a level compatible with the development of the more functional Ly6C− CD11b+ DC subset. Presence of E2 had no effect on progenitors from either knock-in mice with 7-aa deletion in helix 12 of ERα, lacking AF-2, or ERα−/− mice. By contrast, in Flt3 ligand–driven DC differentiation, activation of AF-1 domain was required to promote the development of more functionally competent conventional DCs and pDCs. Moreover, lack of ERα AF-1 blunted the TLR7-mediated IFN-α response of female pDCs in vivo. Thus, our study demonstrates that ERα uses AF-1 differently in steady-state and inflammatory DC lineages to regulate their innate functions, suggesting that selective ER modulators could be used to target specific DC subsets.

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…Our data adds to previous reports on the influence of sex on production of IFNα by pDCs, demonstrating that also surface maturation markers are upregulated more in female pDCs (Berghöfer et al, 2006;Meier et al, 2009;Seillet et al, 2012Seillet et al, , 2013. The effect of sex on upregulation of especially CD40 but also CD86 was respectively mostly or partially explained by the rs179008 variant allele.…”

“…Although previous studies found no evidence for incomplete or skewed X-inactivation this was recently challenged by Souyris and colleagues who reported that pDC express more TLR7 in females due to escape of X-inactivation (Schott et al, 2007a;Berghöfer et al, 2006;Souyris et al, 2018). Besides, TLR7 function may be enhanced by female hormones and/or enhanced expression of molecules downstream of TLR7 (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015). It remains unclear why possession of a heterozygous genotype offers an advantage when it comes to pDC maturation and reducing CHB risk.…”

“…pDC function is also affected by sex: male pDCs, as compared to female pDCs, produce less IFNα upon TLR7 but not TLR9 ligation (Berghöfer et al, 2006;Meier et al, 2009). This difference is believed to derive from expression differences of X-chromosomal genes downstream of TLR7, combined with hormonal effects (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015). In addition, chronic HBV (CHB) infection itself can also impair pDC function; HBV impairs IFNα secretion and other pDC functions in response to TLR9 ligation (Woltman et al, 2011;Martinet et al, 2012aMartinet et al, , 2012b.…”

X-Chromosome Complement and Estrogen Receptor Signaling Independently Contribute to the Enhanced TLR7-Mediated IFN-α Production of Plasmacytoid Dendritic Cells from Women

“…The female sex hormone estrogen is a good candidate for explaining the better TLR-mediated responses of human pDCs developing in female HuMice (19,20). Because estrogens mediate their effects through binding to the nuclear ERa and ERb, we examined the ER isotype expression profile of peripheral blood leukocytes including pDCs by quantitative PCR.…”

“…We recently tested the hypothesis that the abundance of the female sex hormone estrogens may regulate TLR responsiveness of pDCs (19,20). We first showed that pDCs from postmenopausal women exhibited a reduced TLR-mediated response as compared with premenopausal women.…”