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

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.