Functional Nrf2 restrains inflammatory and transcriptional phenotypes in microglia and its deficiency recapitulates the aging phenotype

• Published in: The Journal of immunology (1950) 2019-05, Vol.202 (1_Supplement), p.185-185.17
• Main Authors: Yu, I-Chen Ivorine, Paraiso, Hallel C, Kuo, Ping-Chang, Scofield, Barbara A., Sweazey, Robert D., Chang, Fen-Lei, Yen, Jui-Hung
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.202.Supp.185.17

Microglia (MG) represent plastic myeloid cells resident in the brain that can dynamically respond to changes of local microenvironment and stimuli from the periphery. Dysfunctional microglial responses are thought to worsen the pathogenesis of neurodegeneration. The nuclear factor (erythroid-derived 2) - like 2 (Nrf2) protein is a transcription factor that regulates expressions of antioxidant and stress defense genes. Here, we reported that chronic Nrf2 deficiency in MG leads to neuroinflammation and Alzheimer’s disease-like cognitive impairment during aging. The Nrf2 transcript was downregulated in MG from the middle-aged (12 months-old) and aged (24 months-old) brain. Loss of Nrf2 primed MG towards inflammatory phenotype as revealed the significant increase of Clec7a and CD68 markers. Middle-aged Nrf2 knockout (Nrf2−/−) mice showed elevated reactive MG, proinflammatory cytokines, and infiltrating immune cells in the brain, and resembled Alzheimer’s disease like-cognitive impairment in aged mice. Nrf2−/− MG showed increased nuclear NF-κB p65 and CD86 at the resting state, whereas the reduced induction of CD206, Ym1, and Fizz1 after IL-4 stimulation. These results suggested that Nrf2-deficient MG are primed toward inflammatory phenotypes and resistant to the anti-inflammatory modulation. In addition, loss of Nrf2 resulted in downregulation of homeostatic signatures in MG, such as P2ry12, Tmem119, Gpr34, Tgfbr1, and Mafb, suggesting the importance of Nrf2 signaling to regulate microglial homeostasis. Overall, our results demonstrated that functional decline of Nrf2 results in dysregulated phenotypes in MG, which may lead to extravagant neuroinflammation and impaired cognition in aging and Alzheimer’s disease.