Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease

Abstract

It has become clear that the endocannabinoid system is a potent regulator of immune responses, with the cannabinoid receptor 2 (CB2) as the key component due to its high expression by all immune subtypes. CB2 has been shown to regulate immunity by a number of mechanisms including development, migration, proliferation, and effector functions. In addition, CB2 has been shown to modulate the function of all immune cell types examined to date. CB2 is a G(i)-protein-coupled receptor and thus exhibits a complex pharmacology allowing both stimulatory and inhibitory signaling that depends on receptor expression levels, ligand concentration, and cell lineage specificities. Here, we discuss both in vitro and in vivo experimental evidence that CB2 is a potent regulator of immune responses making it a prime target for the treatment of inflammatory diseases.

Figure 1

Signaling pathways induced following CB2 engagement with cannabinoid ligands. Black and red arrows indicate CB2-mediated signaling events, while grey arrows represent other receptor-mediated pathways. CB2 ligation by cannabinoid ligands regulates adenylate cyclase activation (A), which controls PKA activation (B). PKA crosstalks with the TCR signaling pathway attenuating cytokine production (B). CB2 ligation also directly activates MAPK resulting both the positive and negative regulation of cellular functions (C, D). CB2 signaling can also block MPAK signaling induced by other external stimuli (E).