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Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease

Author

Listed:
  • Tatsuma Ban

    (Yokohama City University Graduate School of Medicine)

  • Masako Kikuchi

    (Yokohama City University Graduate School of Medicine
    Yokohama City University Graduate School of Medicine)

  • Go R. Sato

    (Yokohama City University Graduate School of Medicine)

  • Akio Manabe

    (Yokohama City University Graduate School of Medicine)

  • Noriko Tagata

    (Yokohama City University Graduate School of Medicine)

  • Kayo Harita

    (Yokohama City University Graduate School of Medicine)

  • Akira Nishiyama

    (Yokohama City University Graduate School of Medicine)

  • Kenichi Nishimura

    (Yokohama City University Graduate School of Medicine)

  • Ryusuke Yoshimi

    (Yokohama City University Graduate School of Medicine)

  • Yohei Kirino

    (Yokohama City University Graduate School of Medicine)

  • Hideyuki Yanai

    (University of Tokyo)

  • Yoshiko Matsumoto

    (Tsukuba Research Laboratories, Eisai Co., Ltd.)

  • Shuichi Suzuki

    (Tsukuba Research Laboratories, Eisai Co., Ltd.)

  • Hiroe Hihara

    (Tsukuba Research Laboratories, Eisai Co., Ltd.)

  • Masashi Ito

    (Tsukuba Research Laboratories, Eisai Co., Ltd.)

  • Kappei Tsukahara

    (Tsukuba Research Laboratories, Eisai Co., Ltd.)

  • Kentaro Yoshimatsu

    (Tsukuba Research Laboratories, Eisai Co., Ltd.
    RIN Institute Inc.)

  • Tadashi Yamamoto

    (Okinawa Institute of Science and Technology Graduate University)

  • Tadatsugu Taniguchi

    (University of Tokyo)

  • Hideaki Nakajima

    (Yokohama City University Graduate School of Medicine)

  • Shuichi Ito

    (Yokohama City University Graduate School of Medicine)

  • Tomohiko Tamura

    (Yokohama City University Graduate School of Medicine
    Yokohama City University)

Abstract

The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

Suggested Citation

  • Tatsuma Ban & Masako Kikuchi & Go R. Sato & Akio Manabe & Noriko Tagata & Kayo Harita & Akira Nishiyama & Kenichi Nishimura & Ryusuke Yoshimi & Yohei Kirino & Hideyuki Yanai & Yoshiko Matsumoto & Shui, 2021. "Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24609-4
    DOI: 10.1038/s41467-021-24609-4
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    Cited by:

    1. Andras Boeszoermenyi & Léa Bernaleau & Xudong Chen & Felix Kartnig & Min Xie & Haobo Zhang & Sensen Zhang & Maeva Delacrétaz & Anna Koren & Ann-Katrin Hopp & Vojtech Dvorak & Stefan Kubicek & Daniel A, 2023. "A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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