Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells

Arthritis Res Ther. 2015 Mar 22;17(1):72. doi: 10.1186/s13075-015-0588-3.

Abstract

Introduction: Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level.

Methods: We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies.

Results: Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature.

Conclusions: Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.

MeSH terms

  • Biopsy
  • Blotting, Western
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Gene Expression Regulation*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Interferon Type I / biosynthesis*
  • Interferon-alpha / biosynthesis*
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Lupus Nephritis / genetics*
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology
  • Major Histocompatibility Complex
  • Microscopy, Confocal
  • Proteasome Endopeptidase Complex / biosynthesis
  • Proteasome Endopeptidase Complex / genetics*
  • RNA / genetics*
  • Real-Time Polymerase Chain Reaction
  • Retrospective Studies

Substances

  • Interferon Type I
  • Interferon-alpha
  • RNA
  • LMP7 protein
  • Proteasome Endopeptidase Complex