Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Yiu G

PROVIDER: S-EPMC4848130 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Publications

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

Yiu Gloria G Rasmussen Tue K TK Ajami Bahareh B Haddon David J DJ Chu Alvina D AD Tangsombatvisit Stephanie S Haynes Winston A WA Diep Vivian V Steinman Larry L Faix James J Utz Paul J PJ

Arthritis & rheumatology (Hoboken, N.J.) 20160501 5

<h4>Objective</h4>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 ...[more]

PMID: 26636548

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Project description:BackgroundEnd-stage kidney disease (ESKD) from lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Kidney biopsy is the gold standard for diagnosis and prognostication of LN. While interstitial fibrosis and tubular atrophy (IFTA) predict progression to ESKD, the National Institutes of Health (NIH) classification of interstitial inflammation in unscarred cortical parenchyma is not predictive of chronic kidney disease (CKD) progression. The objective of this study was to determine whether total cortical interstitial inflammation that accounts for inflammation in the entire cortical parenchyma could predict CKD progression in patients with LN. Early identification of at-risk patients may improve outcomes.MethodsThis retrospective cohort study included 125 SLE patients with LN class III, IV, V or mixed (III/V, IV/V) on the index biopsy (2005-2018). Kidney biopsies were reviewed and assigned based on the 2018 NIH Activity Index (AI) and tubulointerstitial lesion categories. Total interstitial inflammation in the entire cortical parenchyma was graded as 0, 1, 2 or 3, corresponding to <10%, 10-25%, 26-50% and >50%, respectively, of the total cortical parenchyma containing an inflammatory infiltrate (similar to the definition used in the Banff total inflammation score). CKD progression was defined as an estimated glomerular filtration rate decrease of ≥30% within 5 years after the index biopsy. Kaplan-Meier survival curves and Cox proportional hazards models were performed to compare the two scoring systems, the total cortical intestinal inflammation score and the NIH interstitial inflammation score as predictors of CKD progression.ResultsOf 125 patients, 46 experienced CKD progression; 21 of 46 subsequently developed ESKD, 28 (22.4%) had moderate-severe total cortical interstitial inflammation and 8 (6.4%) had moderate-severe NIH interstitial inflammation. There were no differences in baseline characteristics between progressors and nonprogressors. Total cortical interstitial inflammation was associated with CKD progression in time-dependent analyses [hazard ratio 2.45 (95% confidence interval 1.2-4.97)] adjusted for age at biopsy, race, sex, LN class and hypertensive vascular change on kidney biopsy. The NIH interstitial inflammation was not associated with CKD progression.ConclusionsIn contrast to the current NIH interstitial inflammation classification, accounting for interstitial inflammation in the entire cortical parenchyma allows identification of patients at risk for CKD progression in LN.

Project description:BackgroundLupus nephritis (LN) is an inflammatory disease of the kidneys affecting patients with systemic lupus erythematosus. Current immunosuppressive and cytotoxic therapies are associated with serious side effects and fail to protect 20-40% of LN patients from end-stage renal disease. In this study, we investigated whether a small heat shock protein, HSPB5, can reduce kidney inflammation and the clinical manifestations of the disease in NZB/W F1 mice. Furthermore, we investigated whether HSPB5 can enhance the effects of methylprednisolone, a standard-of-care drug in LN, in an endotoxemia mouse model.MethodsNZB/W F1 mice were treated with HSPB5, methylprednisolone, or vehicle from 23 to 38 weeks of age. Disease progression was evaluated by weekly proteinuria scores. At the end of the study, the blood, urine, spleens, and kidneys were collected for the assessment of proteinuria, blood urea nitrogen, kidney histology, serum IL-6 and anti-dsDNA levels, immune cell populations, and their phenotypes, as well as the transcript levels of proinflammatory chemokine/cytokines in the kidneys. HSPB5 was also evaluated in combination with methylprednisolone in a lipopolysaccharide-induced endotoxemia mouse model; serum IL-6 levels were measured at 24 h post-endotoxemia induction.ResultsHSPB5 significantly reduced terminal proteinuria and BUN and substantially improved kidney pathology. Similar trends, although to a lower extent, were observed with methylprednisolone treatment. Serum IL-6 levels and kidney expression of BAFF, IL-6, IFNγ, MCP-1 (CCL2), and KIM-1 were reduced, whereas nephrin expression was significantly preserved compared to vehicle-treated mice. Lastly, splenic Tregs and Bregs were significantly induced with HSPB5 treatment. HSPB5 in combination with methylprednisolone also significantly reduced serum IL-6 levels in endotoxemia mice.ConclusionsHSPB5 treatment reduces kidney inflammation and injury, providing therapeutic benefits in NZB/W F1 mice. Given that HSPB5 enhances the anti-inflammatory effects of methylprednisolone, there is a strong interest to develop HSBP5 as a therapeutic for the treatment of LN.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

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