title: Bcl-2 antagonists kill plasmacytoid dendritic cells from lupus-prone mice and dampen interferon-α production.
abstract: OBJECTIVE
  Interferon-α (IFNα)-producing plasmacytoid dendritic cells (PDCs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). IFNα-related genes are highlighted among SLE susceptibility alleles and are characteristically expressed in the blood of patients with SLE, while in mouse models of lupus, PDC numbers and IFNα production are increased. This study was undertaken to investigate the effects of inhibitors that selectively target different antiapoptotic molecules on the survival of PDCs.
  
  
  METHODS
  PDC numbers, in vitro survival, and expression of antiapoptotic molecules were evaluated in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice. The impact of Bcl-2 antagonists and glucocorticoids on PDCs was evaluated in vitro and in vivo. IFNα production by NZB/NZW mice was evaluated before and after treatment with Bcl-2 antagonists.
  
  
  RESULTS
  PDCs, but not lymphoid tissue-resident conventional DCs, largely relied on the antiapoptotic protein Bcl-2 for survival. The enlarged PDC compartment in NZB/NZW mice was associated with selectively prolonged survival and increased Bcl-2 transcription. Functionally, this resulted in enhanced production of IFNα. Bcl-2 inhibitors selectively killed mouse and human PDCs, including PDCs from SLE patients, but not conventional DCs, dampened IFNα production by PDCs, and synergized with glucocorticoids to kill activated PDCs.
  
  
  CONCLUSIONS
  Enhanced PDC survival is a likely contributing factor to enhanced IFNα production by lupus PDCs. Bcl-2 antagonists potently and selectively kill PDCs and reduce IFNα production. Thus, we believe that they are attractive candidates for treating PDC-associated diseases.
authors.affiliation: The Walter & Eliza Hall Institute of Medical Research and University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Emma M
authors.initials: EM
authors.lastname: Carrington
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Ko
authors.forename: Ingela B
authors.initials: IB
authors.lastname: Vikstrom
authors.forename: Shereen
authors.initials: S
authors.lastname: Oon
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Vremec
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Brady
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Ian P
authors.initials: IP
authors.lastname: Wicks
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000974:Antibodies, Antinuclear / Q000097:blood; D001713:Biphenyl Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D017304:Annexin A5; D000974:Antibodies, Antinuclear; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005938:Glucocorticoids; D016898:Interferon-alpha; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C052617:Bcl2 protein, mouse; C579720:venetoclax