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Sanmarco, Liliana M; Wheeler, Michael A; Gutiérrez-Vázquez, Cristina; Polonio, Carolina Manganeli; Linnerbauer, Mathias; Pinho-Ribeiro, Felipe A; Li, Zhaorong; Giovannoni, Federico; Batterman, Katelyn V; Scalisi, Giulia; Zandee, Stephanie E J; Heck, Evelyn S; Alsuwailm, Moneera; Rosene, Douglas L; Becher, Burkhard; Chiu, Isaac M; Prat, Alexandre; Quintana, Francisco J
Nature (London), 02/2021, Letnik: 590, Številka: 7846Journal Article
Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions . However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP1 and the death receptor ligand TRAIL . LAMP1 TRAIL astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1 TRAIL astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ NK cells that are licensed by the microbiome.
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