title: Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.
abstract: Increased IFN-α production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFN-α upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. In this article, we show that basal levels of IFN regulatory factor (IRF) 5 in pDCs were significantly higher in females compared with males and positively correlated with the percentage of IFN-α-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFN-α secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced Irf5 mRNA expression in pDCs and IFN-α production. IRF5 mRNA levels furthermore correlated with ESR1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by ESR1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFN-α production upon TLR7 stimulation in females and provide novel targets for the modulation of immune responses and inflammation.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Centre d'Immunonologie et des Maladies Infectieuses-Paris, Université Pierre et Marie Curie/INSERM U1135, Hôpital Pitié Salpêtrière, Paris 75013, France;
authors.forename: Morgane
authors.initials: M
authors.lastname: Griesbeck
authors.affiliation: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg 20246, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: INSERM U1043, Toulouse F-31300, France; CNRS, U5282, Toulouse F-31300, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffont
authors.affiliation: Chemistry and Biology, Nucleotides and Immunology for Therapy, CNRS UMR-8601, Université Paris Descartes, Paris 75270, France;
authors.forename: Nikaïa
authors.initials: N
authors.lastname: Smith
authors.affiliation: Institut Pasteur, Unité de recherche associée CNRS 3015, Unite Virus et Immunité, Paris 75015, France;
authors.forename: Lise
authors.initials: L
authors.lastname: Chauveau
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Phillip
authors.identifier: http://orcid.org/0000-0003-1864-4130
authors.initials: P
authors.lastname: Tomezsko
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139;
authors.forename: Armon
authors.initials: A
authors.lastname: Sharei
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Georgio
authors.initials: G
authors.lastname: Kourjian
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Filippos
authors.identifier: http://orcid.org/0000-0002-6345-9316
authors.initials: F
authors.lastname: Porichis
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Meghan
authors.initials: M
authors.lastname: Hart
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Christine D
authors.initials: CD
authors.lastname: Palmer
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Michael
authors.initials: M
authors.lastname: Sirignano
authors.affiliation: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg 20246, Germany; Medical Department, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Beisel
authors.affiliation: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg 20246, Germany;
authors.forename: Heike
authors.initials: H
authors.lastname: Hildebrandt
authors.affiliation: INSERM U1043, Toulouse F-31300, France; CNRS, U5282, Toulouse F-31300, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France;
authors.forename: Claire
authors.identifier: http://orcid.org/0000-0001-6641-7851
authors.initials: C
authors.lastname: Cénac
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Alexandra-Chloé
authors.initials: AC
authors.lastname: Villani
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Thomas J
authors.identifier: http://orcid.org/0000-0002-2798-5909
authors.initials: TJ
authors.lastname: Diefenbach
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
authors.affiliation: Institut Pasteur, Unité de recherche associée CNRS 3015, Unite Virus et Immunité, Paris 75015, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Schwartz
authors.affiliation: Chemistry and Biology, Nucleotides and Immunology for Therapy, CNRS UMR-8601, Université Paris Descartes, Paris 75270, France;
authors.forename: Jean-Philippe
authors.identifier: http://orcid.org/0000-0001-8114-8012
authors.initials: JP
authors.lastname: Herbeuval
authors.affiliation: Centre d'Immunonologie et des Maladies Infectieuses-Paris, Université Pierre et Marie Curie/INSERM U1135, Hôpital Pitié Salpêtrière, Paris 75013, France;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.affiliation: INSERM U1043, Toulouse F-31300, France; CNRS, U5282, Toulouse F-31300, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France;
authors.forename: Jean-Charles
authors.identifier: http://orcid.org/0000-0003-4499-3270
authors.initials: JC
authors.lastname: Guéry
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Department of Infectious Diseases, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: J Judy
authors.initials: JJ
authors.lastname: Chang
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg 20246, Germany; marcus.altfeld@hpi.uni-hamburg.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7