Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Type I interferons (IFN-I) are crucial for effective antimicrobial defense in the central nervous system (CNS) but also can cause severe neurological disease (termed cerebral interferonopathy) as exemplified by Aicardi-Goutières Syndrome. In the CNS, microglia and astrocytes have essential roles in host responses to infection and injury, with both cell types responding to IFN-I. While the IFN-I signaling pathways are the same in astrocytes and microglia, the extent to which the IFN-I responses of these cells differ, if at all, is unknown. Here we determined the global transcriptional responses of astrocytes and microglia to the IFN-I, IFN-α. We found that under basal conditions, each cell type has a unique gene expression pattern reflective of its developmental origin and biological function. Following stimulation with IFN-α, astrocytes and microglia also displayed a common core response that was characterized by the increased expression of genes required for pathogen detection and elimination. Compared with astrocytes, microglia had a more extensive and diverse response to IFN-α with significantly more genes with expression upregulated (282 vs. 141) and downregulated (81 vs. 3). Further validation was documented for selected IFN-I-regulated genes in a murine model of cerebral interferonopathy. In all, the findings highlight not only overlapping but importantly divergent responses to IFN-I by astrocytes versus microglia. This suggests specialized roles for these cells in host defense and in the development of cerebral interferonopathy.