A TRAIL from gut to brain

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Science Signaling  23 Feb 2021:
Vol. 14, Issue 671, eabh1677
DOI: 10.1126/scisignal.abh1677

Natural killer cells licensed by gut microbiota drive a population of TRAIL+ astrocytes to limit inflammation in the brain.

Astrocytes are glial cells that play diverse roles in the central nervous system (CNS), including regulating neural activity and providing metabolic support. Dysregulation of astrocyte function underlies many neurological diseases and neuroinflammation. Noting the diversity in the subsets and functional states of astrocytes, Sanmarco et al. investigated a potential anti-inflammatory role for these cells. Flow cytometry analysis revealed that lysosomal-associated membrane protein 1 (LAMP1) was the most abundant marker on mouse spinal cord astrocytes and its abundance was further increased in a mouse model of multiple sclerosis, EAE. Knockout of LAMP1 in astrocytes worsened the symptoms of EAE and led to increased numbers of proinflammatory CD4+ T cells in the CNS. LAMP1-deficient mouse astrocytes had less cell surface TRAIL, a death receptor ligand. Knockout of TRAIL in mouse astrocytes led to decreased activation of pro-apoptotic caspase-3 in CNS-recruited CD4+ T cells and phenocopied the effects of loss of LAMP1 in EAE mice. Single-cell RNA-seq analysis of LAMP1+TRAIL+ astrocytes in naïve mice revealed a transcriptional signature associated with signaling by the cytokine IFN-γ. Treatment of astrocytes with IFN-γ in vitro increased TRAIL mRNA expression, but this was inhibited by TNF and IL-1α, proinflammatory cytokines that are produced by CNS-recruited CD4+ T cells during EAE. Immunostaining and in situ hybridization revealed that TRAIL+ astrocytes localized near IFN-γ–producing natural killer (NK) cells in the meninges of naïve mice. Depletion of these NK cells reduced the number of TRAIL+ astrocytes in the meninges. Noting that the intestinal microbiome induces IFN-γ production in NK cells, the authors found that germ-free mice had fewer IFN-γ+ NK cells and TRAIL+ astrocytes in the meninges than did specific pathogen-free mice. Finally, antibiotic depletion and fecal microbiota transfer experiments confirmed that the microbiome was required to maintain the number of TRAIL+ astrocytes in the meninges. Cell-tracking experiments showed that NK cells migrated from the small intestine to the meninges and that antibiotic treatment reduced the expression of IFN-γ in those cells. Together, these data suggest that microbiome-licensed IFN-γ+ NK cells maintain a TRAIL+ population of astrocytes in the CNS that induces T cell apoptosis to reduce inflammation.

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