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J Immunol. 2015 Dec 1;195(11):5327-36. doi: 10.4049/jimmunol.1501684. Epub 2015 Oct 30.

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.

Author information

1
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;
2
Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg 20246, Germany;
3
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;
4
Chemistry and Biology, Nucleotides and Immunology for Therapy, CNRS UMR-8601, Université Paris Descartes, Paris 75270, France;
5
Institut Pasteur, Unité de recherche associée CNRS 3015, Unite Virus et Immunité, Paris 75015, France;
6
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
7
The David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139;
8
Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg 20246, Germany; Medical Department, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany;
9
Broad Institute of MIT and Harvard, Cambridge, MA 02139; and.
10
Centre d'Immunonologie et des Maladies Infectieuses-Paris, Université Pierre et Marie Curie/INSERM U1135, Hôpital Pitié Salpêtrière, Paris 75013, France;
11
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Department of Infectious Diseases, Monash University, Melbourne, Victoria 3800, Australia.
12
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.

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.

PMID:
26519527
PMCID:
PMC4654231
DOI:
10.4049/jimmunol.1501684
[Indexed for MEDLINE]
Free PMC Article

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