Dataset Information

Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation

ABSTRACT: Astrocytes adapt to injury and disease by entering reactive states with altered gene expression, morphology, and function, but we still do not know how these states evolve over time in human cells or whether they acquire immune effector properties. Using human cortical organoids (hCOs) and primary fetal cortical tissue, we mapped the temporal dynamics and plasticity of inflammatory human astrocytes. Brief and prolonged exposure to inflammatory cytokines elicited robust, time-dependent changes in astrocyte transcriptomes and chromatin accessibility, and these exposures produced distinct acute and chronic reactive signatures. Despite these widespread genomic alterations, astrocytes that experienced either acute or chronic cytokine exposure reverted to a quiescent gene expression and chromatin state within days of cytokine withdrawal, which demonstrates a high degree of plasticity. Chronic inflammatory settings, but not acute ones, revealed a second layer of reactivity in which astrocytes induced major histocompatibility complex class II (MHCII) genes and surface MHCII protein. We validated MHCII expression and surface localization in primary human fetal astrocytes, in organotypic fetal cortical slices that include microglia, and in human brain tissue from patients with chronic inflammatory lesions. We propose that delayed MHCII emergence reflects progressive activation of interferon linked signaling in astrocytes, including low level interferon gamma production. Through co-immunoprecipitation and mass spectrometry of MHCII complexes from TIC-treated fetal astrocytes we identified candidate MHCII-presented peptides and confirmed that astrocytes can process and display exogenous peptides derived from human fetal neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313768 | GEO | 2026/04/15

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

Dataset Information

Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets