The CB2 Receptor in Immune Regulation and Disease: Genetic Architecture, Epigenetic Control, and Emerging Therapeutic Strategies

The cannabinoid receptor type 2 (CB2) is increasingly recognized as a crucial regulator of neuroimmune balance in the brain. In addition to its well-established role in immunity, the CB2 receptor has been identified in specific populations of neurons and glial cells throughout various brain regions, and its expression is dynamically increased during inflammatory and neuropathological conditions, positioning it as a potential non-psychoactive target for modifying neurological diseases. The expression of the CB2 gene (CNR2) is finely tuned by epigenetic processes, including promoter CpG methylation, histone modifications, and non-coding RNAs, which regulate receptor availability and signaling preferences in response to stress, inflammation, and environmental factors. CB2 signaling interacts with TRP channels (such as TRPV1), nuclear receptors (PPARγ), and orphan G Protein-Coupled Receptors (GPCRs, including GPR55 and GPR18) within the endocannabinoidome (eCBome), influencing microglial characteristics, cytokine production, and synaptic activity. We review how these interconnected mechanisms affect neurodegenerative and neuropsychiatric disorders, underscore the species- and cell-type-specificities that pose challenges for translation, and explore emerging strategies, including selective agonists, positive allosteric modulators, and biased ligands, that leverage the signaling adaptability of the CB2 receptor while reducing central effects mediated by the CB1 receptor. This focus on the neuro-centric perspective repositions the CB2 receptor as an epigenetically informed, context-dependent hub within the eCBome, making it a promising candidate for precision therapies in conditions featuring neuroinflammation.