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

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2015 Nov 1

PMID 26519527

Citations 129

Authors

Morgane Griesbeck

Susanne Ziegler

Sophie Laffont

Nikaia Smith

Lise Chauveau

Phillip Tomezsko

Armon Sharei

Georgio Kourjian

Filippos Porichis

Meghan Hart

Christine D Palmer

Michael Sirignano

Claudia Beisel

Heike Hildebrandt

Claire Cenac

Alexandra-Chloe Villani

Thomas J Diefenbach

Sylvie Le Gall

Olivier Schwartz

Jean-Philippe Herbeuval

Brigitte Autran

Jean-Charles Guery

J Judy Chang

Marcus Altfeld

Affiliations

Soon will be listed here.

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.

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References

Klein S . The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev. 2000; 24(6):627-38. DOI: 10.1016/s0149-7634(00)00027-0. View

Barnes B, Moore P, Pitha P . Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem. 2001; 276(26):23382-90. DOI: 10.1074/jbc.M101216200. View

Lelu K, Laffont S, Delpy L, Paulet P, Perinat T, Tschanz S . Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J Immunol. 2011; 187(5):2386-93. DOI: 10.4049/jimmunol.1101578. View

Taniguchi K, Ito Y, Sugito N, Kumazaki M, Shinohara H, Yamada N . Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms. Sci Rep. 2015; 5:8647. PMC: 4342556. DOI: 10.1038/srep08647. View

Grossman C . Interactions between the gonadal steroids and the immune system. Science. 1985; 227(4684):257-61. DOI: 10.1126/science.3871252. View

Graham R, Kozyrev S, Baechler E, Reddy M, Plenge R, Bauer J . A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet. 2006; 38(5):550-5. DOI: 10.1038/ng1782. View

Du X, Li X, Li L, Xu Y, Feng Y . The detection of ESR1/PGR/ERBB2 mRNA levels by RT-QPCR: a better approach for subtyping breast cancer and predicting prognosis. Breast Cancer Res Treat. 2013; 138(1):59-67. DOI: 10.1007/s10549-013-2432-2. View

Weinstein Y, Ran S, Segal S . Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse. J Immunol. 1984; 132(2):656-61. View

Cao W, Manicassamy S, Tang H, Kasturi S, Pirani A, Murthy N . Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol. 2008; 9(10):1157-64. PMC: 3732485. DOI: 10.1038/ni.1645. View

10.

Dieguez-Gonzalez R, Calaza M, Perez-Pampin E, Rodriguez de la Serna A, Fernandez-Gutierrez B, Castaneda S . Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis. Arthritis Rheum. 2008; 58(5):1264-74. DOI: 10.1002/art.23426. View

11.

Sharei A, Zoldan J, Adamo A, Sim W, Cho N, Jackson E . A vector-free microfluidic platform for intracellular delivery. Proc Natl Acad Sci U S A. 2013; 110(6):2082-7. PMC: 3568376. DOI: 10.1073/pnas.1218705110. View

12.

Hedl M, Abraham C . IRF5 risk polymorphisms contribute to interindividual variance in pattern recognition receptor-mediated cytokine secretion in human monocyte-derived cells. J Immunol. 2012; 188(11):5348-56. PMC: 3409850. DOI: 10.4049/jimmunol.1103319. View

13.

Mitchell L . Sex differences in antibody- and cell-mediated immune response to rubella re-immunisation. J Med Microbiol. 1999; 48(12):1075-1080. DOI: 10.1099/00222615-48-12-1075. View

14.

Meier A, Alter G, Frahm N, Sidhu H, Li B, Bagchi A . MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol. 2007; 81(15):8180-91. PMC: 1951290. DOI: 10.1128/JVI.00421-07. View

15.

Grebely J, Page K, Sacks-Davis R, Schim van der Loeff M, Rice T, Bruneau J . The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology. 2013; 59(1):109-20. PMC: 3972017. DOI: 10.1002/hep.26639. View

16.

Ozato K, Tailor P, Kubota T . The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem. 2007; 282(28):20065-9. DOI: 10.1074/jbc.R700003200. View

17.

Honda K, Takaoka A, Taniguchi T . Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity. 2006; 25(3):349-60. DOI: 10.1016/j.immuni.2006.08.009. View

18.

Seillet C, Laffont S, Tremollieres F, Rouquie N, Ribot C, Arnal J . The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling. Blood. 2011; 119(2):454-64. DOI: 10.1182/blood-2011-08-371831. View

19.

Green M, Shohat T, Lerman Y, Cohen D, Slepon R, Duvdevani P . Sex differences in the humoral antibody response to live measles vaccine in young adults. Int J Epidemiol. 1994; 23(5):1078-81. DOI: 10.1093/ije/23.5.1078. View

20.

Teijaro J, Ng C, Lee A, Sullivan B, Sheehan K, Welch M . Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science. 2013; 340(6129):207-11. PMC: 3640797. DOI: 10.1126/science.1235214. View