Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor that has neuroprotective and anti-inflammatory effects, regulating more than 250 genes. As NRF2, cannabinoid receptor type 2 (CB2) is also implicated in the preservation of neurons against glia-driven inflammation. To this concern, little is known about the regulation pathways implicated in CB2 receptor expression. In this study, we analyze whether NRF2 could modulate the transcription of CB2 in neuronal and microglial cells. Bioinformatics analysis revealed an antioxidant response element in the promoter sequence of the CB2 receptor gene. Further analysis by chemical and genetic manipulations of this transcription factor demonstrated that NRF2 is not able to modulate the expression of CB2 in neurons. On the other hand, at the level of microglia, the expression of CB2 is NRF2-dependent. These results are related to the differential levels of expression of both genes regarding the brain cell type. Since modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neurodegeneration, our findings will contribute to disclose the potential of CB2 as a novel target for treating different pathologies.
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This work was supported by the Spanish Ministry of Economy and Competitiveness (Grants Refs. SAF2016-76520-R to ILB and BFU2016-75973-R to MDG).
All experiments were performed by certified researchers according to regional, national, and European regulations concerning animal welfare and animal experimentation, and were authorized by the Ethics Committee for Research of the Universidad Autónoma de Madrid and the Comunidad Autónoma de Madrid, Spain, with Ref PROEX 279/14 and Ref PROEX 221/14, following institutional, Spanish and European guidelines (Boletín Oficial del Estado (BOE) of 18 March 1988 and 86/609/EEC, 2003/65/EC European Council Directives). The housing facilities at the Institute were approved by Comunidad de Madrid (# ES 280790000188) and comply with official regulations.
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Galán-Ganga, M., del Río, R., Jiménez-Moreno, N. et al. Cannabinoid CB2 Receptor Modulation by the Transcription Factor NRF2 is Specific in Microglial Cells. Cell Mol Neurobiol 40, 167–177 (2020). https://doi.org/10.1007/s10571-019-00719-y
- CB2 receptor
- Dimethyl fumarate (DMF)