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bioRxiv · 10.1101/500918

Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice

Rohraff, D. M.·He, Y.·Farkash, E. A.·Schonfeld, M.·Tsou, P.-S.·Sawalha, A. H.
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Abstract

ObjectivesWe previously revealed a role for EZH2 in inducing pro-inflammatory epigenetic changes in lupus CD4+ T cells. In this study, we sought to determine if inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.\n\nMethodsEZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and mRNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by DZNep intraperitoneal administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-dsDNA antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.\n\nResultsEZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy.\n\nLymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep treated mice. Concentrations of circulating cytokines and chemokines, including TNF, IFN-{gamma}, CCL2, RANTES/CCL5, IL-10, KC/CXCL1, IL-12, IL-12p40 and MIP-1{beta}/CCL4 were decreased in DZNep treated mice.\n\nConclusionsZH2 is upregulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option in lupus patients.

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Rohraff, D. M., He, Y., Farkash, E. A., Schonfeld, M., Tsou, P.-S., Sawalha, A. H.. 2018-12-25. Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice. https://doi.org/10.1101/500918

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