title: 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.
authors.affiliation: INSERM U1043, Toulouse F-31300, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.forename: Nelly
authors.initials: N
authors.lastname: Rouquié
authors.forename: Eliane
authors.initials: E
authors.lastname: Foulon
authors.forename: Victorine
authors.initials: V
authors.lastname: Douin-Echinard
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Guéry
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffont
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D018845:CD11 Antigens; D004958:Estradiol; D047628:Estrogen Receptor alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D051193:Toll-Like Receptors; D000099218:Interferon Regulatory Factor-4; C084881:flt3 ligand protein