Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain
Summary: Nrf2 is a promising therapeutic target for neurological disorders, but its mechanisms of action remain unclear. While often linked to anti-inflammatory effects, this is mostly based on studies involving pharmacological activation. In the brain, Nrf2 is highly expressed in microglia, astrocy...
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Elsevier
2025-09-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225014592 |
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| author | Xin He Owen Dando Jing Qiu |
| author_facet | Xin He Owen Dando Jing Qiu |
| author_sort | Xin He |
| collection | DOAJ |
| description | Summary: Nrf2 is a promising therapeutic target for neurological disorders, but its mechanisms of action remain unclear. While often linked to anti-inflammatory effects, this is mostly based on studies involving pharmacological activation. In the brain, Nrf2 is highly expressed in microglia, astrocytes, and endothelial cells. 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. We discovered that in healthy brains, Nrf2 controls distinct transcriptional profiles in the three brain cell types under study. Surprisingly, after systemic inflammation, microglia, and astrocytes lacking Nrf2 showed reduced inflammatory responses, unlike endothelial cells. Additionally, even without any insult, Nrf2 in microglia supported the expression of pro-inflammatory genes. Our findings reveal a pro-inflammatory role for endogenous Nrf2 in specific brain cell types. |
| format | Article |
| id | doaj-art-ff49f753ec2d464882b18fb2add2cf23 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-ff49f753ec2d464882b18fb2add2cf232025-08-20T04:00:55ZengElsevieriScience2589-00422025-09-0128911319810.1016/j.isci.2025.113198Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brainXin He0Owen Dando1Jing Qiu2UK Dementia Research Institute, University of Edinburgh, Edinburgh Medical School, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UKUK Dementia Research Institute, University of Edinburgh, Edinburgh Medical School, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UKUK Dementia Research Institute, University of Edinburgh, Edinburgh Medical School, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Corresponding authorSummary: Nrf2 is a promising therapeutic target for neurological disorders, but its mechanisms of action remain unclear. While often linked to anti-inflammatory effects, this is mostly based on studies involving pharmacological activation. In the brain, Nrf2 is highly expressed in microglia, astrocytes, and endothelial cells. 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. We discovered that in healthy brains, Nrf2 controls distinct transcriptional profiles in the three brain cell types under study. Surprisingly, after systemic inflammation, microglia, and astrocytes lacking Nrf2 showed reduced inflammatory responses, unlike endothelial cells. Additionally, even without any insult, Nrf2 in microglia supported the expression of pro-inflammatory genes. Our findings reveal a pro-inflammatory role for endogenous Nrf2 in specific brain cell types.http://www.sciencedirect.com/science/article/pii/S2589004225014592biological sciencesneurosciencemolecular neuroscience |
| spellingShingle | Xin He Owen Dando Jing Qiu Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain iScience biological sciences neuroscience molecular neuroscience |
| title | Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain |
| title_full | Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain |
| title_fullStr | Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain |
| title_full_unstemmed | Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain |
| title_short | Nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell-type specific manner in the adult mouse brain |
| title_sort | nrf2 controls homeostatic transcriptional signatures and inflammatory responses in a cell type specific manner in the adult mouse brain |
| topic | biological sciences neuroscience molecular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225014592 |
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