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

J Immunol. 2015 Dec 1;195(11):5327-36. doi: 10.4049/jimmunol.1501684. Epub 2015 Oct 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Regulation
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Interferon Regulatory Factors / pharmacology
  • Interferon-alpha / biosynthesis*
  • Interferon-alpha / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • RNA, Messenger / biosynthesis
  • Recombinant Proteins / pharmacology
  • Sex Characteristics*
  • Signal Transduction / genetics
  • Toll-Like Receptor 7 / metabolism*


  • Estrogen Receptor alpha
  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Interferon-alpha
  • RNA, Messenger
  • Recombinant Proteins
  • TLR7 protein, human
  • Toll-Like Receptor 7