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

被引：186

作者：

Griesbeck, Morgane ^{[1
,2
]}

Ziegler, Susanne ^{[3
]}

Laffont, Sophie ^{[4
,5
,6
]}

Smith, Nikaia ^{[7
]}

Chauveau, Lise ^{[8
]}

Tomezsko, Phillip ^{[1
]}

Sharei, Armon ^{[9
]}

Kourjian, Georgio ^{[1
]}

Porichis, Filippos ^{[1
]}

Hart, Meghan ^{[1
]}

Palmer, Christine D. ^{[1
]}

Sirignano, Michael ^{[1
]}

Beisel, Claudia ^{[10
]}

Hildebrandt, Heike ^{[3
]}

Cenac, Claire ^{[4
,5
,6
]}

Villani, Alexandra-Chloe ^{[11
]}

Diefenbach, Thomas J. ^{[1
]}

Le Gall, Sylvie ^{[1
]}

Schwartz, Olivier ^{[8
]}

Herbeuval, Jean-Philippe ^{[7
]}

Autran, Brigitte ^{[2
]}

Guery, Jean-Charles ^{[4
,5
,6
]}

Chang, J. Judy ^{[1
,12
]}

Altfeld, Marcus ^{[1
,3
]}

机构：

[1] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA

[2] Univ Paris 06, Hop La Pitie Salpetriere, INSERM, Ctr Immunonol & Malad Infect Paris,U1135, F-75013 Paris, France

[3] Leibniz Inst Expt Virol, Heinrich Pette Inst, D-20246 Hamburg, Germany

[4] INSERM, U1043, F-31300 Toulouse, France

[5] CNRS, U5282, F-31300 Toulouse, France

[6] Univ Toulouse 3, Ctr Physiopathol Toulouse Purpan, F-31300 Toulouse, France

[7] Univ Paris 05, CNRS UMR 8601, Chem & Biol, Nucleotides & Immunol Therapy, F-75270 Paris, France

[8] Inst Pasteur, Unite Rech Associee, CNRS 3015, Unite Virus & Immunite, F-75015 Paris, France

[9] David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[10] Univ Hosp Hamburg Eppendorf, Dept Med, D-20246 Hamburg, Germany

[11] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA

[12] Monash Univ, Dept Infect Dis, Melbourne, Vic 3800, Australia

来源：

JOURNAL OF IMMUNOLOGY | 2015年 / 195卷 / 11期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

INTERFERON REGULATORY FACTOR; ESTROGEN-RECEPTOR-ALPHA; NF-KAPPA-B; I INTERFERON; INTERFERON-REGULATORY-FACTOR-5; GENE; ANTIVIRAL RESPONSES; MEDIATED RESPONSE; IMMUNE-RESPONSES; GONADAL-STEROIDS; BREAST-CANCER;

D O I：

10.4049/jimmunol.1501684

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：5327 / 5336

页数：10

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