Development of Th17-Associated Interstitial Kidney Inflammation in Lupus-Prone Mice Lacking the Gene Encoding STAT-1 ARTHRITIS & RHEUMATOLOGY Yiu, G., Rasmussen, T. K., Ajami, B., Haddon, D. J., Chu, A. D., Tangsombatvisit, S., Haynes, W. A., Diep, V., Steinman, L., Faix, J., Utz, P. J. 2016; 68 (5): 1233-1244

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-a/ß/? 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 ?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.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.

View details for DOI 10.1002/art.39535

View details for Web of Science ID 000375551600023

View details for PubMedID 26636548

View details for PubMedCentralID PMC4848130