TY - JOUR
T1 - Development of Th17-Associated Interstitial Kidney Inflammation in Lupus-Prone Mice Lacking the Gene Encoding STAT-1
AU - Yiu, Gloria
AU - Rasmussen, Tue K.
AU - Ajami, Bahareh
AU - Haddon, David J.
AU - Chu, Alvina D.
AU - Tangsombatvisit, Stephanie
AU - Haynes, Winston A.
AU - Diep, Vivian
AU - Steinman, Larry
AU - Faix, James
AU - Utz, Paul J.
N1 - Funding Information:
Supported by the NIH (grant 1 S10 OD 0105800A1 and National Heart, Lung, and Blood Institute Proteomics contract HHSN 288201000034C), the Lupus Foundation of America, the Alliance for Lupus Research (grant 21858), the Stanford Institute for Immunity, Transplantation, and Infection (pilot grant), FP grant 261, and the Henry Gustav Floren Foundation (gift to Dr. Utz). Ms Yiu's work was supported by the Stanford Medical Scientist Training Program. Dr. Rasmussen's work was supported by the Novo Nordisk Foundation, the Danish Rheumatoid Association, and The Graduate School of Health, Aarhus University. Dr. Utz is recipient of a Donald E. and Delia B. Baxter Foundation Career Development Award.
Publisher Copyright:
© 2016, American College of Rheumatology.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
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U2 - 10.1002/art.39535
DO - 10.1002/art.39535
M3 - Article
C2 - 26636548
AN - SCOPUS:84964570069
SN - 2326-5191
VL - 68
SP - 1233
EP - 1244
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 5
ER -