He Xin, Dando Owen, Qiu Jing
UK 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.
iScience. 2025 Jul 25;28(9):113198. doi: 10.1016/j.isci.2025.113198. eCollection 2025 Sep 19.
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.
核因子E2相关因子2（Nrf2）是神经疾病一个很有前景的治疗靶点，但其作用机制仍不清楚。虽然它常与抗炎作用相关，但这大多基于涉及药理学激活的研究。在大脑中，Nrf2在小胶质细胞、星形胶质细胞和内皮细胞中高度表达。迄今为止，Nrf2在调节基础转录组和控制神经炎症方面的脑细胞类型特异性作用尚不清楚。为了解决这个问题，我们使用了三种诱导型条件性Nrf2基因敲除小鼠，其中Nrf2分别在小胶质细胞、星形胶质细胞和脑内皮细胞中被敲除。我们发现，在健康大脑中，Nrf2控制着所研究的三种脑细胞类型中不同的转录谱。令人惊讶的是，在全身炎症后，与内皮细胞不同，缺乏Nrf2的小胶质细胞和星形胶质细胞显示出炎症反应减弱。此外，即使没有任何损伤，小胶质细胞中的Nrf2也支持促炎基因的表达。我们的研究结果揭示了内源性Nrf2在特定脑细胞类型中的促炎作用。
