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Microglia, the brain's resident immune cells, undergo age\u2010associated changes that disrupt neuroimmune homeostasis and exacerbate neuroinflammation. The transcription factor Nuclear Factor Erythroid 2\u2010Related 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\u2010deficient (\n                    <jats:italic>Nrf2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    ) mice exhibit amplified microglial activation, elevated MHC class II\u2010related CD74 expression, and enhanced infiltration of peripheral CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells into the brain.\n                    <jats:italic>Nrf2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    microglia adopt a disease\u2010associated microglia (DAM)\u2010like phenotype, characterized by upregulated activation markers and transcriptional reprogramming. Functionally, Nrf2 loss impairs motor learning and cognitive performance in middle\u2010aged mice. To dissect the role of microglial Nrf2, we generated microglia\u2010specific Nrf2 knockout (MG\u2010Nrf2\u2010KO) mice using a Cx3cr1\u2010CreERT2 system. MG\u2010Nrf2\u2010KO mice exhibit exaggerated microglial immune training characterized by elevated brain TNF\u03b1 and IL\u20101\u03b2 production upon secondary LPS challenge, despite preserved peripheral immune tolerance. The heightened training response is accompanied by reduced IL\u201010 expression in MG\u2010Nrf2\u2010KO brains, indicating impaired anti\u2010inflammatory counter\u2010regulation. Ex\u00a0vivo restimulation confirms that Nrf2\u2010deficient microglia intrinsically produce elevated pro\u2010IL\u20101\u03b2 protein upon rechallenge, establishing Nrf2 as a cell\u2010autonomous 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.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501457rr","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:04:04Z","timestamp":1764140644000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microglial Nrf2 Functions as a Cell\u2010Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4577-3831","authenticated-orcid":false,"given":"Hallel C.","family":"Paraiso","sequence":"first","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine  Fort Wayne Indiana 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