title: Development of Th17-Associated Interstitial Kidney Inflammation in Lupus-Prone Mice Lacking the Gene Encoding STAT-1.
abstract: Type I interferon (IFN) signaling is a central pathogenic pathway in systemic lupus erythematosus (SLE), and therapeutics targeting type I IFN signaling are in development. Multiple proteins with overlapping functions play a role in IFN signaling, but the signaling events downstream of receptor engagement are unclear. This study was undertaken to investigate the roles of the type I and type II IFN signaling components IFN-α/β/ω receptor 2 (IFNAR-2), IFN regulatory factor 9 (IRF-9), and STAT-1 in a mouse model of SLE.
  
  
  
  We used immunohistochemical staining and highly multiplexed assays to characterize pathologic changes in histology, autoantibody production, cytokine/chemokine profiles, and STAT phosphorylation in order to investigate the individual roles of IFNAR-2, IRF-9, and STAT-1 in MRL/lpr mice.
  
  
  
  We found that STAT-1(-/-) mice, but not IRF-9(-/-) or IFNAR-2(-/-) mice, developed interstitial nephritis characterized by infiltration with retinoic acid receptor-related orphan nuclear receptor γt-positive lymphocytes, macrophages, and eosinophils. Despite pronounced interstitial kidney disease and abnormal kidney function, STAT-1(-/-) mice had decreased proteinuria, glomerulonephritis, and autoantibody production. Phosphospecific flow cytometry revealed shunting of STAT phosphorylation from STAT-1 to STAT-3/4.
  
  
  
  We describe unique contributions of STAT-1 to pathology in different kidney compartments in a mouse model, and provide potentially novel insight into tubulointerstitial nephritis, a poorly understood complication that predicts end-stage kidney disease in SLE patients.
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Gloria
authors.initials: G
authors.lastname: Yiu
authors.affiliation: Stanford University School of Medicine, Stanford, California, and Aarhus University, Aarhus, Denmark.
authors.forename: Tue K
authors.initials: TK
authors.lastname: Rasmussen
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Ajami
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: David J
authors.identifier: 0000-0002-3687-264X
authors.initials: DJ
authors.lastname: Haddon
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Alvina D
authors.initials: AD
authors.lastname: Chu
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tangsombatvisit
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Winston A
authors.initials: WA
authors.lastname: Haynes
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Vivian
authors.initials: V
authors.lastname: Diep
authors.affiliation: Stanford University School of Medicine and Institute for Immunity, Transplantation, and Infection, Stanford, California.
authors.forename: Larry
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: James
authors.initials: J
authors.lastname: Faix
authors.affiliation: Stanford University School of Medicine and Institute for Immunity, Transplantation, and Infection, Stanford, California.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001323:Autoantibodies / Q000276:immunology; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011507:Proteinuria / Q000235:genetics / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics* / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007371:Interferon-gamma; D053633:Receptor, Interferon alpha-beta; D050794:STAT1 Transcription Factor; C508034:Ifnar2 protein, mouse; C494080:Stat1 protein, mouse; C494228:Isgf3g protein, mouse