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

• Published in: The Journal of immunology (1950) Vol. 195; no. 11; pp. 5327 - 5336
• Main Authors: Griesbeck, Morgane, Ziegler, Susanne, Laffont, Sophie, Smith, Nikaïa, Chauveau, Lise, Tomezsko, Phillip, Sharei, Armon, Kourjian, Georgio, Porichis, Filippos, Hart, Meghan, Palmer, Christine D, Sirignano, Michael, Beisel, Claudia, Hildebrandt, Heike, Cénac, Claire, Villani, Alexandra-Chloé, Diefenbach, Thomas J, Le Gall, Sylvie, Schwartz, Olivier, Herbeuval, Jean-Philippe, Autran, Brigitte, Guéry, Jean-Charles, Chang, J Judy, Altfeld, Marcus
• Format: Journal Article
• Language: English
• Published: United States Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists 01.12.2015; AAI
• Subjects: Animals; Cells, Cultured; Dendritic Cells - immunology; Estrogen Receptor alpha - genetics; Female; Gene Expression Regulation; Humans; Innate Immunity and Inflammation; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interferon Regulatory Factors - pharmacology; Interferon-alpha - biosynthesis; Interferon-alpha - secretion; Life Sciences; Male; Mice; Mice, Transgenic; Recombinant Proteins - pharmacology; RNA, Messenger - biosynthesis; Sex Characteristics; Signal Transduction - genetics; Toll-Like Receptor 7 - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501684

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.