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

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.

Effects of Systolic Blood Pressure on Brain Integrity in Multiple Sclerosis.

Background: In MS patients, hypertension is associated with a delayed diagnosis and an increased risk of progression. Understanding the mechanisms of this association could potentially lead to improved prevention of disease progression. We aimed to establish whether high blood pressure contributes to white-matter injury and brain atrophy in MS. Methods: Cross-sectional study of 95 patients with RRMS. Estimates of fractional anisotropy, gray-matter volume and lesion load were obtained from 3T MRI. We used fractional anisotropy voxel-based statistics to establish the effect of blood pressure on white matter tracts. Additionally, we used voxel-based morphometry (VBM) to study the effect on gray matter integrity. Results: Only 29.5% had normal blood pressure levels, with 52.6% suffering from prehypertension and 17.9% with hypertension. Increasing systolic blood pressure was associated with damage to posterior white-matter tracts as well as greater levels of gray matter atrophy, in particular in the frontal cortex. Age-adjusted linear regression indicated that neither lesion volume (ß = 0.002, 95%CI: 0.02-0.02; p = 0.85) or lesion number (ß = -0.004, 95%CI: 0.03-0.02; p = 0.74) were associated with systolic blood pressure. Conclusions: Prehypertension and hypertension are frequent in MS. Increased blood pressure is related to white- and gray-matter integrity, both related to MS disability outcomes. These findings suggest attention to the control of blood pressure in MS patients.