Microglial Nrf2 Functions as a Cell‐Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain

Aging is the primary risk factor for Alzheimer's disease (AD) and related dementias, with chronic neuroinflammation contributing to disease progression. Microglia, the brain's resident immune cells, undergo age-associated changes that disrupt neuroimmune homeostasis and exacerbate neuroinflammation. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), a master regulator of cellular stress responses, has an undefined role in microglial aging. We demonstrate that Nrf2 mRNA expression and protein decline in aged microglia, coinciding with increased neuroinflammation and antigen presentation. Global Nrf2-deficient (Nrf2^-/-) mice exhibit amplified microglial activation, elevated MHC class II-related CD74 expression, and enhanced infiltration of peripheral CD4⁺ T cells into the brain. Nrf2^-/- microglia adopt a disease-associated microglia (DAM)-like phenotype, characterized by upregulated activation markers and transcriptional reprogramming. Functionally, Nrf2 loss impairs motor learning and cognitive performance in middle-aged mice. To dissect the role of microglial Nrf2, we generated microglia-specific Nrf2 knockout (MG-Nrf2-KO) mice using a Cx3cr1-CreERT2 system. MG-Nrf2-KO mice exhibit exaggerated microglial immune training characterized by elevated brain TNFα and IL-1β production upon secondary LPS challenge, despite preserved peripheral immune tolerance. The heightened training response is accompanied by reduced IL-10 expression in MG-Nrf2-KO brains, indicating impaired anti-inflammatory counter-regulation. Ex vivo restimulation confirms that Nrf2-deficient microglia intrinsically produce elevated pro-IL-1β protein upon rechallenge, establishing Nrf2 as a cell-autonomous regulator of microglial immune memory. These findings identify Nrf2 as an intrinsic regulator of microglial immune memory and neuroinflammatory restraint. Modulating Nrf2 signaling in microglia may offer a therapeutic strategy to mitigate chronic neuroinflammation and cognitive decline in aging and neurodegeneration.