Aicardi-Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5

Hideo Onizawa, Hiroki Kato, Hiroyuki Kimura, Tomoo Kudo, Nobumasa Soda, Shota Shimizu, Masahide Funabiki, Yusuke Yagi, Yuji Nakamoto, Josef Priller, Ryuta Nishikomori, Toshio Heike, Nan Yan, Tohru Tsujimura, Tsuneyo Mimori, Takashi Fujita

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


MDA5 is a cytoplasmic sensor of viral RNA, triggering type I interferon (IFN-I) production. Constitutively active MDA5 has been linked to autoimmune diseases such as systemic lupus erythematosus, Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome (AGS), a genetically determined inflammatory encephalopathy. However, AGS research is challenging due to the lack of animal models. We previously reported lupus-like nephritis and SMS-like bone abnormalities in adult mice with constitutively active MDA5 (Ifih1G821S/+), and herein demonstrate that these mice also exhibit high lethality and spontaneous encephalitis with high IFN-I production during the early postnatal period. Increases in the number of microglia were observed in MDA5/MAVS signaling-and IFN-I-dependent manners. Furthermore, microglia showed an activated state with an increased phagocytic capability and reduced expression of neurotrophic factors. Although multiple auto-Antibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients, Ifih1G821S/+Rag2-/- mice also exhibited up-regulation of IFN-I, astrogliosis and microgliosis, indicating that auto-Antibodies or lymphocytes are not required for the development of the encephalitis. The IFN-I signature without lymphocytic infiltration observed in Ifih1G821S/+ mice is a typical feature of AGS. Collectively, our results suggest that the Ifih1G821S/+ mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy.

Original languageEnglish (US)
Pages (from-to)225-240
Number of pages16
JournalInternational Immunology
Issue number4
StatePublished - Apr 1 2021


  • astrocyte
  • microglia
  • type I interferon

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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