Aicardi–Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5. (9th November 2020)

• Record Type: Journal Article
• 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
• Is Part Of: International immunology. Volume 33:Number 4(2021)
• Page Start: 225
• Page End: 240
• Publication Date: 2020-11-09
• Subjects: astrocyte -- microglia -- type I interferon; Immunology -- Periodicals; 616.079
• DOI: 10.1093/intimm/dxaa073
• Languages: English
• ISSNs: 0953-8178

Abstract

Abstract : A reliable model for Aicardi-Goutières syndrome 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.