title: The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling.
abstract: Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/β) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7-mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7-mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17β-estradiol markedly enhances TLR-7- and TLR-9-dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) α. Genetic ablation of ERα gene in the DC lineage abrogated the enhancing effect of 17β-estradiol on their TLR-mediated production of IFN-α, showing that estrogens directly target pDCs in vivo. Our results uncover a previously unappreciated role for estrogens in regulating the innate functions of pDCs, which may account for sex-based differences in autoimmune and infectious diseases.
authors.affiliation: Inserm, U, Toulouse, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffont
authors.forename: Florence
authors.initials: F
authors.lastname: Trémollières
authors.forename: Nelly
authors.initials: N
authors.lastname: Rouquié
authors.forename: Claude
authors.initials: C
authors.lastname: Ribot
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Victorine
authors.initials: V
authors.lastname: Douin-Echinard
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Guéry
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D017698:Postmenopause; D015398:Signal Transduction / Q000187:drug effects*; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D047628:Estrogen Receptor alpha; D007370:Interferon Type I; D016898:Interferon-alpha; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D004958:Estradiol