title: Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells.
abstract: OBJECTIVE
  To investigate the hypothesis that proteasome inhibition may have potential in the treatment of SLE, by targeting plasmacytoid dendritic cells (PDCs) and plasma cells, both of which are critical in disease pathogenesis.
  
  
  METHODS
  Lupus-prone mice were treated with the nonselective proteasome inhibitors carfilzomib and bortezomib, the immunoproteasome inhibitor ONX 0914, or vehicle control. Tissue was harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by evaluation for proteinuria and by histologic analysis of kidneys. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay (ELISA), and total IgG and dsDNA antibody-secreting cells (ASCs) by enzyme-linked immunospot assay. Human peripheral blood mononuclear cells or mouse bone marrow cells were incubated with Toll-like receptor (TLR) agonists and proteasome inhibitors, and interferon-α (IFNα) levels were measured by ELISA and flow cytometry.
  
  
  RESULTS
  Early treatment of lupus-prone mice with the dual-targeting proteasome inhibitors carfilzomib or bortezomib or the immunoproteasome-specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells, with greater reductions in autoreactive than in total IgG ASCs, an effect that became more pronounced with prolonged treatment and was reflected in decreasing serum autoantibody levels. Notably, proteasome inhibition efficiently suppressed production of IFNα by TLR-activated PDCs in vitro and in vivo, an effect mediated by inhibition of both PDC survival and PDC function.
  
  
  CONCLUSIONS
  Inhibition of the immunoproteasome is equally efficacious as dual targeting agents in preventing lupus disease progression by targeting 2 critical pathways in disease pathogenesis, type I IFN activation and autoantibody production by plasma cells.
authors: University of Rochester Medical Center, Rochester, New York, USA.
authors: H Travis
authors: HT
authors: Ichikawa
authors: Thomas
authors: T
authors: Conley
authors: Tony
authors: T
authors: Muchamuel
authors: Jing
authors: J
authors: Jiang
authors: Susan
authors: S
authors: Lee
authors: Teresa
authors: T
authors: Owen
authors: Jennifer
authors: J
authors: Barnard
authors: Sarah
authors: S
authors: Nevarez
authors: Bruce I
authors: BI
authors: Goldman
authors: Christopher J
authors: CJ
authors: Kirk
authors: R John
authors: RJ
authors: Looney
authors: Jennifer H
authors: JH
authors: Anolik
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000187:drug effects* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D018450:Disease Progression; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001323:Autoantibodies; D001897:Boronic Acids; D007370:Interferon Type I; D009842:Oligopeptides; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; C524865:carfilzomib