Inhibition of IRF5 hyperactivation protects from lupus onset and severity
Su Song, Saurav De, Victoria Nelson, Samin Chopra, Margaret LaPan, Kyle Kampta, Shan Sun, Mingzhu He, Cherrie D. Thompson, Dan Li, Tiffany Shih, Natalie Tan, Yousef Al-Abed, Eugenio Capitle, Cynthia Aranow, Meggan Mackay, William L. Clapp, Betsy J. Barnes
Su Song, Saurav De, Victoria Nelson, Samin Chopra, Margaret LaPan, Kyle Kampta, Shan Sun, Mingzhu He, Cherrie D. Thompson, Dan Li, Tiffany Shih, Natalie Tan, Yousef Al-Abed, Eugenio Capitle, Cynthia Aranow, Meggan Mackay, William L. Clapp, Betsy J. Barnes
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Research Article Autoimmunity Immunology

Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Abstract

The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum–induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.

Authors

Su Song, Saurav De, Victoria Nelson, Samin Chopra, Margaret LaPan, Kyle Kampta, Shan Sun, Mingzhu He, Cherrie D. Thompson, Dan Li, Tiffany Shih, Natalie Tan, Yousef Al-Abed, Eugenio Capitle, Cynthia Aranow, Meggan Mackay, William L. Clapp, Betsy J. Barnes

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Figure 8

N5-1 inhibits SLE serum–induced IRF5 activation and reverses IRF5 hyperactivation in SLE immune cells.

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N5-1 inhibits SLE serum–induced IRF5 activation and reverses IRF5 hypera...
(A) Healthy donor PBMCs (n = 6) were preincubated with an inhibitor (10 μM) followed by stimulation with 2% SLE serum for 2 hours. The percentage of IRF5 nuclear translocation is shown in pDCs (A), monocytes (B), and B cells (C) from imaging flow cytometry. (D and E) Correlation between the percentage of IRF5 translocation in SLE serum–stimulated monocytes (D) or B cells (E) and in vivo IRF5 activation in matched SLE monocytes or B cells, respectively, by linear regression analysis. (F) SLE PBMCs were mock or inhibitor treated (10 μM) for 1 hour, and IRF5 activation in monocytes and B cells was quantified by imaging flow cytometry. The percentage of IRF5 nuclear translocation is shown. Data represent the mean ± SEM. Differences between groups were determined by 2-way ANOVA with Bonferroni’s multiple-comparison test. *P ≤ 0.05 and **P ≤ 0.01.