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- Title
Aicardi–Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5.
- Authors
Onizawa, Hideo; Kato, Hiroki; Kimura, Hiroyuki; Kudo, Tomoo; Soda, Nobumasa; Shimizu, Shota; Funabiki, Masahide; Yagi, Yusuke; Nakamoto, Yuji; Priller, Josef; Nishikomori, Ryuta; Heike, Toshio; Yan, Nan; Tsujimura, Tohru; Mimori, Tsuneyo; Fujita, Takashi
- Abstract
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 (Ifih1 G821S/+ ), 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, Ifih1 G821S/+ 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 Ifih1 G821S/+ mice is a typical feature of AGS. Collectively, our results suggest that the Ifih1 G821S/+ mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy.
- Subjects
TYPE I interferons; SYSTEMIC lupus erythematosus; ENCEPHALITIS; MICE; AUTOANTIBODIES
- Publication
International Immunology, 2021, Vol 33, Issue 4, p225
- ISSN
0953-8178
- Publication type
Article
- DOI
10.1093/intimm/dxaa073