Integrated meta-analysis of human astrocytes transcriptomes reveals a candidate recurrent inflammatory signature in response to inflammatory and immune stimuli

Abstract

Astrocytes are key regulators of inflammatory and immune responses in the central nervous system, particularly under pathological conditions. We conducted a systematic search of the NCBI GEO and ENA databases to identify transcriptomic studies of stimulated astrocytes. This meta-analysis integrates 11 RNA-Seq datasets, encompassing a total of 153 samples (91 stimulated, and 62 controls) exposed to pro-inflammatory stimuli such as cytokines (TNF-α, IL-6, and IL-1β), palmitic acid, and pathogens like SARS-CoV-2 and Borrelia burgdorferi. Through robust rank aggregation (RRA), we identified 130 differentially expressed genes (DEGs), including 125 upregulated and 5 downregulated. Functional enrichment analyses revealed that these DEGs are primarily involved in immune and inflammatory pathways, such as cytokine signaling, interferon responses, and NF-κB activation. Network analysis revealed five hub nodes, CXCL10, DDX58, IFIH1, IL-1β, and TLR3, underscoring their importance in astrocytic inflammatory signaling. These findings emphasize the ability of astrocytes to act as immunocompetent cells that coordinate inflammatory responses through mechanisms such as the NOD-like receptor and NF-κB pathways. Although chronic activation of NF-κB has been linked to inflammation, this pathway also plays essential roles in synaptic plasticity. Moreover, the consistent upregulation of DDX58 and IFIH1 across varied inflammatory stimuli suggests that astrocytes transition into a common ‘reactive’ state that may contribute to chronic neuroinflammation. This study identifies a candidate gene signature and underscores the dual protective and pathological roles of astrocytes in inflammatory processes.