Cannabinoid CB₂ Receptor Modulation by the Transcription Factor NRF2 is Specific in Microglial Cells

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.