research HIGHLIGHTS

NEUROIMMUNOLOGY MAFG activity in astrocytes drives CNS­ inf­ lammation­ Astrocytes contribute to the patho­ related to pro-inflammatory and of Mat2a ameliorates disease in mice genesis of multiple sclerosis, but the neurotoxic pathways, such as the with EAE. Mice with an astrocyte- astrocytes in mechanistic basis of this is poorly NF-κB, GM-CSF and iNOS signalling specific deletion of the GM-CSF the active white understood. A new study from the pathways and the unfolded also showed reduced EAE Quin­tana laboratory describes a response. Further analysis showed that disease and this was associated with matter lesions potentially pathological­ role for this Gfap+ astrocyte subpopulation decreased expression of Mafg, Mat2a of patients a subpopulation of astrocytes that showed decreased expression of NRF2 and pro-inflammatory pathways in with multiple are characterized by decreased target , and this was linked to astrocytes. Expression of GM-CSF by sclerosis expression of the antioxidant the increased pro-inflammatory CNS-infiltrating T cells preceded the NRF2 and expression seen in these astrocytes. downregulation of NRF2 and upregu- showed increased expression of MAFG, Accordingly, targeted deletion of lation of Maf and Mat2a, suggesting increased a member of the (sMAF) NRF2 in Gfap+ cells was associated a key role for GM-CSF in promoting MAFG and transcription factor family. with heightened CNS inflammation the pathogenicity of astrocytes in the decreased Wheeler et al. used single-cell and more severe EAE. inflamed CNS. RNA sequencing (scRNA-seq) to The authors used RibotagGfap mice Finally, the authors conducted NRF2 compare astrocytes isolated from to identify additional regulators of scRNA-seq analyses on CNS expression the central nervous system (CNS) of these astrocytes in the inflamed CNS. samples from patients with multiple control mice with those from mice They found that peak EAE disease sclerosis. Similarly to their findings with experimental auto­immune coincided with decreased expression in mice, they identified an astrocyte encephalomyelitis (EAE). They of NRF2-driven genes and increased population that was markedly identified multiple cell populations levels of MAFG. MAFG interacts with expanded in the CNS of patients with that differed between control mice other to regulate gene expres- multiple sclerosis and characterized and mice with EAE, including sion, with MAFG–NRF2 hetero­ by decreased NRF2 activation, along several subpo­pulations of astrocytes. dimers promoting NRF2-driven gene with increased MAFG activation, The most expanded subpopulation of expression and MAFG homodimers DNA methylation, GM-CSF astrocytes in the inflamed CNS was a suppressing NRF2-driven genes. signalling and pro-inflammatory population of Gfap+ astrocytes, which Notably, inactivation of Mafg in astro- pathway activity. Moreover, were chara­cterized by cytes ameliorated EAE and this was astrocytes in the active white matter the expression of genes associated with increased expression lesions of patients with multiple of NRF2 target genes and decreased sclerosis showed increased MAFG pro-inflammatory . and decreased NRF2 expression. Therefore, decreased expression The authors propose that of NRF2 and increased expression of in the inflamed CNS, reduced MAFG in astrocytes seems to promote NRF2 expression enables MAFG CNS inflammation during EAE. and MAT2α to drive epigenetic MAFG has been shown to changes in astrocytes that promote

cooperate with DNA methyltrans- pathological activity, with GM-CSF C

r ferase 3B (DNMT3B) to limit gene from infiltrating T cells amplifying e

d

i this pro-inflammatory programme. t expression and, in keeping with this,

:

S

. the authors showed that inactivation Targeting this pathway could B

r a d of Mafg decreased DNA methylation therefore enable the suppression b r o o at NRF2 target genes. They also of neurotoxic astrocyte activity in k / S p identified a role for the sMAF cofactor multiple sclerosis. r in g e methionine adenosyltransferase IIα Yvonne Bordon r N a tu (MAT2α), which generates substrates re Original article Wheeler, M. A. et al. Lim ited for DNA methylation. They found MAFG-driven astrocytes promote CNS that Mafg and Mat2a are coexpres­sed inflammation. Nature https://doi.org/10.1038/ s41586-020-1999-0 (2020) in astrocytes and that inactivation

NAtuRe RevIews | IMMuNoloGy volume 20 | APRIL 2020 | 205