2. Academic Validation
  3. Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease

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

  • Nat Commun. 2021 Jul 19;12(1):4379. doi: 10.1038/s41467-021-24609-4.
Tatsuma Ban  # 1,  Masako Kikuchi  # 2 3,  Go R Sato  # 2,  Akio Manabe 2,  Noriko Tagata 2,  Kayo Harita 2,  Akira Nishiyama 2,  Kenichi Nishimura 3,  Ryusuke Yoshimi 4,  Yohei Kirino 4,  Hideyuki Yanai 5,  Yoshiko Matsumoto 6,  Shuichi Suzuki 6,  Hiroe Hihara 6,  Masashi Ito 6,  Kappei Tsukahara 6,  Kentaro Yoshimatsu 6 7,  Tadashi Yamamoto 8,  Tadatsugu Taniguchi 5,  Hideaki Nakajima 4,  Shuichi Ito 3,  Tomohiko Tamura 9 10
Affiliations

Affiliations

  • 1 Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. [email protected].
  • 2 Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 3 Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 4 Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 5 Department of Inflammology, Social Cooperation Program, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
  • 6 Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • 7 RIN Institute Inc., Tokyo, Japan.
  • 8 Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
  • 9 Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. [email protected].
  • 10 Advanced Medical Research Center, Yokohama City University, Yokohama, Japan. [email protected].
  • # Contributed equally.
PMID: 34282144 DOI: 10.1038/s41467-021-24609-4
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.

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