Cannabinoid CB(2) 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 (CB(2)) is also implicated in the preservation of neurons against glia-driven inflammation. To this concern, little is known about the regulation pathways implicated in CB(2) receptor expression. In this study, we analyze whether NRF2 could modulate the transcription of CB(2) in neuronal and microglial cells. Bioinformatics analysis revealed an antioxidant response element in the promoter sequence of the CB(2) receptor gene. Further analysis by chemical and genetic manipulations of this transcription factor demonstrated that NRF2 is not able to modulate the expression of CB(2) in neurons. On the other hand, at the level of microglia, the expression of CB(2) is NRF2-dependent. These results are related to the differential levels of expression of both genes regarding the brain cell type. Since modulation of CB(2) 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 CB(2) as a novel target for treating different pathologies.