4.5 Article

Development of Th17-Associated Interstitial Kidney Inflammation in Lupus-Prone Mice Lacking the Gene Encoding STAT-1

期刊

ARTHRITIS & RHEUMATOLOGY
卷 68, 期 5, 页码 1233-1244

出版社

WILEY
DOI: 10.1002/art.39535

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资金

  1. NIH [1-S10-OD-0105800A1]
  2. NIH (National Heart, Lung, and Blood Institute Proteomics) [HHSN-288201000034C]
  3. Lupus Foundation of America
  4. Alliance for Lupus Research [21858]
  5. Stanford Institute for Immunity, Transplantation, and Infection (pilot grant), FP [261]
  6. Henry Gustav Floren Foundation
  7. Stanford Medical Scientist Training Program
  8. Novo Nordisk Foundation
  9. Danish Rheumatoid Association
  10. Graduate School of Health, Aarhus University
  11. Donald E. and Delia B. Baxter Foundation Career Development Award

向作者/读者索取更多资源

Objective. 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-alpha/beta/omega receptor 2 (IFNAR-2), IFN regulatory factor 9 (IRF-9), and STAT-1 in a mouse model of SLE. Methods. 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. Results. 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 gamma t-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. Conclusion. 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.

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