| First Author | Onizawa H | Year | 2020 |
| Journal | Int Immunol | PubMed ID | 33165593 |
| Mgi Jnum | J:300370 | Mgi Id | MGI:6501899 |
| Doi | 10.1093/intimm/dxaa073 | Citation | Onizawa H, et al. (2020) Aicardi-Goutieres syndrome-like encephalitis in mutant mice with constitutively active MDA5. Int Immunol |
| abstractText | 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-Goutieres 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 autoantibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients, Ifih1 G821S/+Rag2 -/- mice also exhibited upregulation of IFN-I, astrogliosis and microgliosis, indicating that autoantibodies 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. |
