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

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 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.

Amanita muscaria extract potentiates production of proinflammatory cytokines by dsRNA-activated human microglia

“…MDA5 is also a cytosolic dsRNA receptor. MDA5 has been shown to play a role in autoimmune diseases such as inflammatory encephalopathy and Aicardi-Goutieres syndrome where microglia are activated and show increased phagocytosis ( Onizawa et al, 2021 ). The precise expression pattern and function of these two dsRNA sensors is still poorly understood in microglia.…”

Advantages of CRISPR-Cas9 combined organoid model in the study of congenital nervous system malformations

“…Seven gene mutations, including TREX1, RNASEH2B, and RNASEH2C have been identified to cause AGS (Rice et al, 2013). The lack of a reliable animal model of AGS hinders the research of disease physiology and treatment (Onizawa et al, 2021). Therefore, when Thomas et al used iPSCs derived from AGS patients to study brain organoids, they found many nerve cell death and nerve cell inflammation, which is similar to clinical neurodegeneration and eventually leads to microcephaly (Thomas et al, 2017).…”

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

“…Pathological signs are associated with increased type I interferon (IFN-α) activity and lymphocytosis in the cerebrospinal fluid and serum and activation of IFN-related downstream signaling [ 142 ]. Astrocytes are the major source of IFN-α in CNS; thus, they were recently proposed as the main players in AGS pathogenesis [ 44 ], though their contribution to the myelin/oligodendrocyte damage is still not clarified [ 52 , 143 ]. Current hypotheses on astrocyte-driven AGS myelin deficits are that mutated, suffering astrocytes are no longer able to support survival/proliferation and myelination capacity of oligodendrocytes and that mutated, activated astrocytes negatively influence OPC maturation due to the detrimental release of IFN-α and inflammatory cytokines [ 139 ].…”

“…To study AGS pathogenesis, many cellular and animal models were developed ( Figure 5 ), including several null mice for the genes involved in AGS (KO), mice expressing the human mutations (KIN) ( TREX1 KO and KIN, RNASEH2A/B/C KO, RNASEH2A/B KIN, SAMHD1 KO, ADAR1 KO, IFIH1 KIN) and some zebrafish models ( SAMDH1 and ADAR1 KO). However, many of these models showed embryonic lethality, while the other did not have an overt brain phenotype ([ 33 ] and references therein) [ 143 ]. Indeed, lab mice live in relatively sterile environments and lack the initial viral stimulus that may trigger the type I interferon response, condition that can explain the absence of neuroinflammation in these animals [ 33 ].…”