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bioRxiv · 10.1101/2024.11.14.623657

Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain

He, X.·Dando, O. R.·Qiu, J.
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Abstract

Nrf2 is an attractive potential therapeutic target for various neurological disorders including neurodegenerative diseases. The mechanisms behind Nrf2-mediated cytoprotection are incompletely understood, however, an anti-inflammatory effect is a popular hypothesis, based primarily on studies where the prior pharmacological activation of Nrf2 has suppressed subsequent responses to inflammatory insults. In the adult brain, Nrf2 is highly expressed in microglia, astrocytes and brain endothelial cells, with minimal expression in neurons. As yet, the brain cell type-specific role of Nrf2 in regulating the basal transcriptome and controlling neuroinflammation is unknown. To address this, we employed three inducible conditional Nrf2 knockout mice in which Nrf2 is deleted in microglia, astrocytes, and brain endothelial cells respectively in a tamoxifen-inducible manner. We discovered that in the healthy brain Nrf2 controls distinct transcriptional signatures in the three brain cell types under study. Surprisingly, following a systemic inflammatory challenge, we found that Nrf2-deficient microglia and astrocytes (but not endothelial cells) both mount a suppressed inflammatory response compared to wild type cells. Moreover, comparison of Nrf2-deficient with wild-type microglia revealed that even in the absence of any insult, microglial Nrf2 supports basal activity of inflammation response genes. Thus, our study uncovers a novel cell type-specific role for endogenous Nrf2 activity in supporting inflammatory responses in the brain.

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He, X., Dando, O. R., Qiu, J.. 2024-11-14. Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain. https://doi.org/10.1101/2024.11.14.623657

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