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

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.

SUBMITTER: Sanmarco LM 

PROVIDER: S-EPMC8039910 | biostudies-literature |

REPOSITORIES: biostudies-literature