Details

Autor(en) / Beteiligte

• Yiu, Gloria
• Rasmussen, Tue K.
• Ajami, Bahareh
• Haddon, David J.
• Chu, Alvina D.
• Tangsombatvisit, Stephanie
• Haynes, Winston A.
• Diep, Vivian
• Steinman, Larry
• Faix, James
• Utz, Paul J.

Titel

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

Ist Teil von

• Arthritis & rheumatology (Hoboken, N.J.), 2016-05, Vol.68 (5), p.1233-1244

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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‐α/β/ω 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 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. 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.