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 - 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 -