Functional Nrf2 restrains inflammatory and transcriptional phenotypes in microglia and is lost in aging
Hallel C. Paraiso1, Ping-Chang Kuo2, Barbara A. Scofield2, Robert D. Sweazey1, Jui-Hung Yen2, Fen-Lei Chang3, I-Chen Yu1 * 1Dep. of Anatomy and Cell Biology, 2Microbiology and Immunology, and 3Neurology, Indiana University School of Medicine
Microglia (MG) are highly plastic cells, adopting phenotypes dynamically in response to the local microenvironment and stimuli from the periphery. During aging, MG may acquire distinct phenotype that negatively impact the brain function. The nuclear factor (erythroid-derived 2) - like 2 (Nrf2) is a transcription factor with established functions in antioxidant and stress defense gene expressions. Here, we reported that Nrf2 deficiency leads to dysregulated immuno- and transcriptional phenotypes in MG. MG isolated from the aged brain showed significantly high levels of Clec7a and CD68 surface markers, indicating a predominantly inflammatory phenotype in aged MG. The inflammatory phenotype of aging MG was associated with reduced Nrf2 expressions in the aged brain, and impairment of long-term memory and motor skill learning in aged mice (24 month-old). We found that Nrf2-/- MG are primed to be inflammatory activated and resistant to regulation. Nrf2-/- MG showed increased NF-κB p65 nuclear translocation at the resting state. The expression of CD86 co-stimulatory molecule and inflammatory mediators were up-regulated in Nrf2-/-MG. Microglial phenotype can be modulated by anti-inflammatory cytokines including IL-4. We found that Nrf2-/- MG are resistant to anti-inflammatory polarization induced by IL-4. In addition to inflammatory signatures, loss of Nrf2 resulted in down-regulation of homeostatic signatures, including P2ry12, Tmem119, Gpr34, and Tgfbr1. The Nrf2-/- mice showed long-term memory deficits regardless of immune challenge. Overall, our data indicate that age-associated functional decline of Nrf2 mediates the inflammatory phenotype in aging MG and contributes the cognitive impairment during aging.
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