Summary

Microglia, the innate immune cells of the brain, are exquisitely sensitive to dynamic changes in the brain environment. We used single cell RNA sequencing to define glial responses in the early postnatal somatosensory cortex after partial whisker lesion, revealing transcriptomic shifts in both astrocytes and microglia during the resulting topographic remapping. The most distinct change was the emergence of a type I interferon (IFN-I) responsive microglia population that was rare in the resting cortex but expanded 20-fold after whisker deprivation. The top gene candidate in this cluster, Ifitm3, marked a conserved but transient subset of microglia that were in the process of phagocytosing whole cells. IFITM3 protein identified this subset in vivo, where it was enriched in early microglial phagosomes. Loss of canonical IFN-I signaling in Ifnar1−/− animals resulted in abnormal ‘bubble’ microglia with deficient phagolysosomal processing. In a meta-analysis of transcriptomes, we identified the IFNI signature in microglia across a range of pathologies. We identified phagocytic IFITM3+ microglia in two murine disease models: SARS-CoV-2 infection and Alzheimer’s Disease. These data reveal the potential of transcriptional profiling after defined perturbation to elicit transient microglial states, and identify a novel role for IFN-I signaling in regulating microglial phagocytosis.