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