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.
This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grants R01 AI078784 and P01 AI078897, fellowships from the National Health and Medical Research Council of Australia (Grant 519578 to J.J.C.), a Ragon Fellowship from The Phillip T. and Susan M. Ragon Foundation (to J.J.C.), a fellowship from the French National Agency for Research on AIDS and Viral Hepatitis (Grant 2013-219 to M.G.), the Fondation pour la Recherche Médicale (Grant DEQ2000329169 to J.-C.G.), the Conseil Régional Midi-Pyrénées (J.-C.G.), the Arthritis Fondation Courtin (J.-C.G.), and the Fondation ARC pour la recherche sur le cancer (J.-C.G.).
The online version of this article contains supplemental material.
- Received July 28, 2015.
- Accepted September 30, 2015.
- Copyright © 2015 by The American Association of Immunologists, Inc.
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