IRF5-mediated signaling and implications for SLE

• Genetic variants of IRF5 are associated with increased risk of SLE.
• The effects of IRF5 risk haplotype are not limited to enhanced IFN production.
• IRF5 is involved in M1 macrophage polarization, apoptosis and autoantibody production.
• Dysregulation of IRF5 activity affects various pathogenic pathways in SLE.

Transcription of the type I IFN genes is regulated by members of the Interferon Regulatory Factor (IRF) 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.