Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.
Morgane Griesbeck
(1, 2)
,
Susanne Ziegler
(3)
,
Sophie Laffont
(4)
,
Nikaïa Smith
(5)
,
Lise Chauveau
(6)
,
Phillip Tomezsko
(2)
,
Armon Sharei
(7)
,
Georgio Kourjian
(2)
,
Filippos Porichis
(2)
,
Meghan Hart
(2)
,
Christine D Palmer
(2)
,
Michael Sirignano
(2)
,
Claudia Beisel
(3, 8)
,
Heike Hildebrandt
(3)
,
Claire Cénac
(4)
,
Alexandra-Chloé Villani
(9)
,
Thomas J Diefenbach
(2)
,
Sylvie Le Gall
(2)
,
Olivier Schwartz
(6)
,
Jean-Philippe Herbeuval
(5)
,
Brigitte Autran
(1)
,
Jean-Charles Guéry
(4)
,
J Judy Chang
(10, 2)
,
Marcus Altfeld
(2, 3)
1
CIMI -
Centre d'Immunologie et de Maladies Infectieuses
2 Ragon Institute of MGH, MIT and Harvard
3 Heinrich-Pette-Institut
4 CPTP - Centre de Physiopathologie Toulouse Purpan
5 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
6 Virus et Immunité
7 Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA]
8 Medical Department [Hamburg]
9 BROAD INSTITUTE - Broad Institute of MIT and Harvard
10 Department of Infectious Diseases [Monash]
2 Ragon Institute of MGH, MIT and Harvard
3 Heinrich-Pette-Institut
4 CPTP - Centre de Physiopathologie Toulouse Purpan
5 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
6 Virus et Immunité
7 Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA]
8 Medical Department [Hamburg]
9 BROAD INSTITUTE - Broad Institute of MIT and Harvard
10 Department of Infectious Diseases [Monash]
Sophie Laffont
- Function : Author
- PersonId : 739608
- IdHAL : sophie-laffont
- ORCID : 0000-0003-2319-0217
- IdRef : 118225324
Nikaïa Smith
- Function : Author
- PersonId : 755421
- ORCID : 0000-0002-0202-612X
- IdRef : 203218329
Claire Cénac
- Function : Author
- PersonId : 765719
- ORCID : 0000-0001-6641-7851
Jean-Philippe Herbeuval
- Function : Author
- PersonId : 738881
- IdHAL : jean-philippe-herbeuval
- ORCID : 0000-0001-8114-8012
- IdRef : 070408793
Jean-Charles Guéry
- Function : Author
- PersonId : 1140791
- ORCID : 0000-0003-4499-3270
- IdRef : 066827760
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.