Inhibition of IRF5 hyperactivation protects from lupus onset and severity
Su Song, … , William L. Clapp, Betsy J. Barnes
Su Song, … , William L. Clapp, Betsy J. Barnes
Published September 8, 2020
Citation Information: J Clin Invest. 2020;130(12):6700-6717. https://doi.org/10.1172/JCI120288.
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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 1

IRF5 is hyperactivated in immune cells from patients with SLE and in NZB/W F1 lupus-prone mice.

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IRF5 is hyperactivated in immune cells from patients with SLE and in NZB...
IRF5 activation was assessed by nuclear localization in CD45+CD14+ monocytes (Mo) (A) and CD45+CD19+ B cells (B) from healthy donors and patients with SLE in the New Jersey cohort using imaging flow cytometry. Data represent the percentage of IRF5 nuclear translocation; circles represent independent donors. (C and D) IRF5 localization determined in monocytes (C) and B cells (D) from healthy donors and patients with SLE in the New York cohort with clinically inactive (score = 0/1) or active (score = 2/3) disease. (E and F) Percentage of IRF5 nuclear translocation in monocytes and B cells from patients with SLE stratified by SLEDAI (E) and dsDNA antibody titers (F). (G–K) Correlation between the percentage of IRF5 translocation in B cells or monocytes and dsDNA titers (G and H) or serum IFN-α levels (J and K) by linear regression analysis. (L and M) IRF5 nuclear translocation in CD11b+ monocytes from cohort 1 (L) and cohort 2 (M) consisting of aging female NZB/W F1 and BALB/c mice. Black circles, NZB/W F1 mice; white circles, BALB/c. n = 3 mice/group/cohort. (N) Inhibition of IRF5 activation (10–21 weeks old) by N5-1 in CD11b+ monocytes. (O and P) Same as in L and M, except in B220+ B cells from cohort 1 (O) and cohort 2 (P). (Q) Same as in N, except inhibition of IRF5 activation is shown in B220+ B cells. (R and S) IRF5 translocation in CD3+CD4+ T cells (R) and CD3+CD8+ T cells (S) from aging female NZB/W F1 and BALB/c mice. n = 6 mice/group. Data represent the mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, by 2-way ANOVA with Bonferroni’s post hoc test.