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Title: Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes.

Authors: 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

Published In Nature, (2021 Feb)

Abstract: Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions1. 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 LAMP12 and the death receptor ligand TRAIL3. 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.

PubMed ID: 33408417 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis; Astrocytes/immunology*; Astrocytes/metabolism; Biomarkers; Central Nervous System/immunology; Encephalomyelitis, Autoimmune, Experimental/immunology; Encephalomyelitis, Autoimmune, Experimental/prevention & control; Female; Gastrointestinal Microbiome/immunology*; Homeostasis; Humans; Inflammation/immunology; Inflammation/prevention & control*; Interferon-gamma/immunology*; Killer Cells, Natural/immunology*; Lysosomal Membrane Proteins/metabolism*; Meninges/cytology; Meninges/immunology; Mice; Mice, Inbred C57BL; T-Lymphocytes/cytology; T-Lymphocytes/immunology; TNF-Related Apoptosis-Inducing Ligand/metabolism*

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