Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-alpha Production in Women
JOURNAL OF IMMUNOLOGY
Authors: Griesbeck, Morgane; Ziegler, Susanne; Laffont, Sophie; Smith, Nikaia; Chauveau, Lise; Tomezsko, Phillip; Sharei, Armon; Kourjian, Georgio; Porichis, Filippos; Hart, Meghan; Palmer, Christine D.; Sirignano, Michael; Beisel, Claudia; Hildebrandt, Heike; Cenac, Claire; Villani, Alexandra-Chloe; Diefenbach, Thomas J.; Le Gall, Sylvie; Schwartz, Olivier; Herbeuval, Jean-Philippe; Autran, Brigitte; Guery, Jean-Charles; Chang, J. Judy; Altfeld, Marcus
Abstract
Increased IFN-alpha production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFN-alpha 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-alpha-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFN-alpha 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-alpha 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-alpha production upon TLR7 stimulation in females and provide novel targets for the modulation of immune responses and inflammation.
IRF5-mediated signaling and implications for SLE
CLINICAL IMMUNOLOGY
Authors: Lazzari, Elisa; Jefferies, Caroline A.
Abstract
Transcription of the type I IFN genes is regulated by members of the Interferon Regulatory Factor (IRE) family of transcription factors, composed in humans of 9 distinct proteins. In addition to IRF3 and IRF7, the transcription factor IRF5 has been shown to be involved in type I IFN production and interestingly, polymorphisms of the IRF5 gene in humans can result in risk or protective haplotypes with regard to SLE susceptibility. In addition to regulation of type I IFN expression, IRF5 is involved in other signaling pathways, including IgG switching in B cells, macrophage polarization and apoptosis, and its role in SLE pathogenesis may therefore not be limited to dysregulated control of IFN expression. In this review we will comprehensively discuss the role of IRF5 in immune-mediated responses and its potential multifaceted role in conferring SLE susceptibility. (C) 2014 Published by Elsevier Inc.
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