Acute Neuroinflammation Induces Prolonged Transcriptional Reprogramming in Microglia

Acute neuroinflammation rapidly activates brain immune responses, but its lasting effects on microglia are unclear. Using systemic LPS administration and LCMV-Armstrong infection, we found that blood–brain barrier disruption and cytokine shifts resolved within 30 days, yet microglial recovery was incomplete—marked by persistent numerical loss and an IFN-?–low phenotype in the LPS model and reduced relative abundance in the LCMV model. Single-cell RNA sequencing revealed sustained transcriptional alterations, including disease-associated microglia (DAM) features and a distinct recovery-biased population. These acute signatures overlapped with profiles from Alzheimer's model mice and were enriched in human microglia from multiple sclerosis, Alzheimer's disease, and other neuroinflammatory conditions. Although our observation period was shorter than the chronic course of these diseases, the persistence of disease-like microglial states suggests that transient inflammation can prime the brain for long-term vulnerability. Targeting this primed state may offer new strategies to prevent or mitigate neurodegenerative pathology. Overall design: Immune cells (CD45+) isolated from the whole brain of C57BL/6J mice at 3 days or 30 days post injection of LPS (2mg/kg), and 7 days or 30 days post injection of LCMV (2x105 PFU) were sorted on flow cytometry and used for single cell RNA sequencing. For the LPS-treated group, the PBS group served as the control, whereas for the LCMV-treated group, the RPMI group was used as the control.