UNVEILING THE ROLE OF CB2 RECEPTOR IN BETA-HYDROXYBUTYRATE MEDIATED MODULATION OF MICROGLIAL ANTI-INFLAMMATORY PHENOTYPE

The cannabinoid receptor type 2 (CB2R), primarily expressed in microglia, the brain’s resident immune cells, acts as a central regulator of neuroinflammatory responses. When CB2R is activated it triggers anti‑inflammatory signaling, making it a promising target for modulating microglial function in neuroinflammatory diseases. The ketone body, β-hydroxybutyrate (BHB), is gaining attention as a therapeutic agent for neurodegenerative disorders due to its ability to modulate neuroinflammation and preserve blood–brain barrier integrity. One mechanism by which BHB exerts anti-inflammatory effects is through regulation of microglial function; however, the precise mechanisms remain unclear. Since the role of BHB in this context is unexplored, our aim was to test the hypothesis that BHB anti-inflammatory effects are mediated by CB2R. We used primary mouse microglia, treated with strong pro-inflammatory stimulus lipopolysaccharide (LPS) and showed that BHB helped restore microglia phagocytic function, which was lost during stimulation with LPS and reducedreactive oxygen species (ROS) synthesis.However, these benefits disappeared when CB2R was pharmacologically blocked with inverse agonist AM-630. Importantly, BHB reduced pro-inflammatory gene expression and increased expression of arginase 1 (Arg1), a hallmark of anti-inflammatory responses, which was reversed by CB2R blockade. Moreover, BHB suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signaling, and this effect was negated by CB2R inhibition, suggesting a mechanistic link between BHB and CB2R-dependent pathways. In conclusion, our findings demonstrate that BHB’s anti-inflammatory effects are mediated, at least in part, through CB2R signaling, providing new insight into its therapeutic potential for neuroinflammation.