Article Text

Download PDFPDF

186 NRF2 regulation of the interferon signature in lupus macrophages
  1. Shuhong Han1,
  2. Haoyang Zhuang2,
  3. Pui Lee3,
  4. Mingjia Li4,
  5. Peter Nigrovic5 and
  6. Westley H Reeves6
  1. 1Division of Rheumatology and Clinical Immunology, University of Florida
  2. 21953
  3. 3Div. of Immunology, Boston Children’s Hospital
  4. 4University of Florida
  5. 5Div. of Immunology, Boston Children’s Hospital
  6. 6Division of Rheumatology and Clinical Immunology, University of Florida


Background Peripheral blood cells from two-thirds of adult lupus patients exhibit a gene expression program (interferon signature) attributed to the over-production of interferon (IFN) and other type I IFNs (IFN-I). IFN-I may be involved in the pathogenesis of lupus. Although plasmacytoid dendritic cells produce large amounts of IFN-I, our studies in an experimental lupus model suggest that macrophages and/or monocytes may play an important role in generating the interferon signature. This study sought to define how macrophages influence the interferon signature.

Methods Proinflammatory and anti-inflammatory (pro-resolving) macrophages were isolated from mice with pristane-induced lupus and were analyzed by RNA-sequencing (RNA-Seq) and quantitative PCR (qPCR). Protein expression in macrophage subsets was evaluated by flow cytometry. The role of nuclear factor erythroid 2 like 2 (Nrf2) activators was examined in vivo

Results Transcriptional profiling (RNA-Seq) of CD11b+Ly6G- peritoneal macrophages from mice with experimental lupus unexpectedly indicated a strong interferon signature in proinflammatory (Ly6ChiCD138-), but not anti-inflammatory (Ly6C-CD138+), macrophages exposed to the same IFN-I concentrations. Along with higher IFN-I regulated gene expression, proinflammatory macrophages expressed lower levels of genes regulated by nuclear factor erythroid 2 like 2 (Nrf2) than anti-inflammatory macrophages. Transcript levels of IFN receptor 1 chain (Ifnar1), IFNAR surface staining, and mitochondrial superoxide all were higher in proinflammatory macrophages. Administration of the Nrf2 activator CDDO-Im to lupus mice decreased IFNAR expression, blocked IFN-driven Stat1 phosphorylation, and reduced IFN-regulated gene expression. Thus, the interferon signature in murine lupus critically depends on Nrf2-regulated changes in IFNAR expression in macrophages. Human peripheral blood mononuclear cells exhibited a similar pattern: high IFNAR expression in classical monocytes and lower levels in non-classical monocytes. The data suggest that anti-inflammatory macrophages/monocytes are insensitive to IFN signaling, potentially serving a role in the resolution of inflammation.

Conclusions These studies reveal that the relative abundance of different monocyte/macrophage subsets (proinflammatory vs. anti-inflammatory/pro-resolving) helps determine the magnitude of the interferon signature. In addition to reflecting IFN-I production, the interferon signature critically depends on the Nrf2-regulated responsiveness of macrophages to signaling through the IFNAR. These studies provide a new perspective on the interferon signature that may have implications for understanding the pathogenesis of lupus. In addition, these studies suggest that Nrf2 activators could have a role in the therapy of lupus.

Funding Source(s): NIH

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.