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]

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.

Domains: Life Sciences [q-bio]

Morgane Griesbeck, Susanne Ziegler, Sophie Laffont, Nikaïa Smith, Lise Chauveau, et al.. Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.. Journal of Immunology, 2015, 195 (11), pp.5327-36. ⟨10.4049/jimmunol.1501684⟩. ⟨pasteur-01372393⟩