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

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, Shuichi Suzuki, Hiroe Hihara, Masashi Ito, Kappei Tsukahara, Kentaro Yoshimatsu, Tadashi Yamamoto, Tadatsugu Taniguchi, Hideaki Nakajima, Shuichi Ito and Tomohiko Tamura ()
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Tatsuma Ban: Yokohama City University Graduate School of Medicine
Masako Kikuchi: 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.
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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24609-4

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