Development of Th17-associated interstitial kidney inflammation in lupus-prone mice lacking the gene encoding Signal Transduction and Activator of Transcription-1 (STAT-1)

Type I interferon (IFN-I) signaling is a central pathogenic pathway in Systemic Lupus Erythematosus (SLE), and therapeutics targeting IFN-I signaling are in development. Multiple proteins with overlapping function participate in IFN signaling, but the signaling events downstream of receptor engageme...

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Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2016-05, Vol.68 (5), p.1233-1244
Main Authors: Yiu, Gloria, Rasmussen, Tue Kruse, Ajami, Bahareh, Haddon, David J., Chu, Alvina D., Tangsombatvisit, Stephanie, Haynes, Winston A., Diep, Vivian, Steinman, Larry, Faix, James, Utz, Paul J.
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Language:English
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Summary:Type I interferon (IFN-I) signaling is a central pathogenic pathway in Systemic Lupus Erythematosus (SLE), and therapeutics targeting IFN-I signaling are in development. Multiple proteins with overlapping function participate in IFN signaling, but the signaling events downstream of receptor engagement are unclear. We employed highly-multiplexed assays to characterize autoantibody production, cytokine/chemokine profiles, and Signal Transduction and Activators of Transcription (STAT) phosphorylation to investigate the individual roles of IFNAR2, IRF9 and STAT1 in MRL/ lpr ( lpr ) mice. Surprisingly, we found that Stat1 −/− , but not Irf9 −/− or Ifnar2 −/− mice, developed interstitial nephritis characterized by infiltration with RORγT + lymphocytes, macrophages and eosinophils. Despite pronounced interstitial kidney disease and abnormal kidney function, Stat1 −/− mice had decreased proteinuria, glomerulonephritis and autoantibody production. Phospho-specific flow cytometry (phosphoflow) revealed shunting of STAT phosphorylation from STAT1 to STAT3/4. In summary, we describe unique contributions of STAT1 to pathology in different kidney compartments, and provide novel insight into tubulointerstitial nephritis (TIN) a poorly understood complication that predicts end-stage kidney disease in SLE patients.
ISSN:2326-5191
2326-5205
DOI:10.1002/art.39535