Fate-mapping via Spp1-expression history revealed innate immune memory of microglia imprinted by neonatal injury [Spp1Tdt]

Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and ultimate fate of disease-associated microglia (DAM) remains largely unknown. We established a lineage tracing system, leveraging the expression dynamics of Spp1, which allows for genetic labeling of DAM-like microglia and tracking their behavior during brain injury and recovery. Fate-mapping of Spp1+ microglia in juvenile stroke revealed an irreversible state of reactive microglia that are ultimately eliminated from the injured brain. In contrast, DAM-like microglia in the neonatal context exhibit high plasticity, capable of regaining a homeostatic signature and integrating into the global microglial network after recovery. Furthermore, neonatal injury has a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, by unraveling the fate of DAM-like microglia in various neuropathological conditions, our work highlights the exceptional plasticity and innate immune memory of neonatal microglia. Overall design: To explore the transcriptional dynamics in DAM-like microglia following stroke induction and upon seconday immune challenge, we performed bulk RNA Seq, single cell RNA-Seq and ATAC-Seq of Tdt+ microglia at multiple time points after SIMPLE.