Fate-mapping via Spp1-expression history revealed innate immune memory of microglia imprinted by neonatal injury [Spp1GFP]

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. To further explore the heterogeneity and the underlying molecular signature of microglial reactivity across neurological disorders, we performed bulk RNA Seq and sc RNA-seq of Spp1-GFP+ microglia from four disease models.