Endocannabinoids in immune regulation and immunopathologies

Abstract

Endocannabinoids are key bioactive components of the endocannabinoid system, and the profound influence of endocannabinoids on the modulation of the immune system is being increasingly appreciated. The knowledge of endocannabinoid-immune cell crosstalk will pave the way to therapeutic implications of modulators of this pathway in autoimmune and chronic inflammatory disorders. Endocannabinoids seem to exert both anti-inflammatory and pro-inflammatory effects in specific contexts, based on specific receptor engagement and the downstream signalling pathways involved. In this review, we summarized the biosynthesis, signalling and degradation of two well-studied endocannabinoids-anandamide and 2-arachidonylglycerol in immune cells. Then, we discussed the effects of these two endocannabinoids on the functioning of major innate and adaptive immune cells, along with the choice of receptors employed in such interactions. Finally, we outline our current knowledge on the involvement of anandamide and 2-arachidonylglycerol in context of inflammation, allergies, autoimmunity and metabolic disorders.

Keywords: 2-AG; CB2; anandamide; autoimmunity; endocannabinoids; immune cells; inflammation; metabolic disorder.

FIGURE 1

Biosynthesis, uptake and catabolism of the endocannabinoids—anandamide (AEA) and 2‐AG. Lower panel shows synthesis of endocannabinoids in immune cells in response to different stimuli and through different pathways for different endocannabinoids. Middle panel shows the binding and signalling of endocannabinoids thus released in the responding cells mostly through the cannabinoid receptors CB1R and CB2R, which are G protein‐coupled receptors. Top panel shows the hydrolysis or oxygenation of endocannabinoids in the cytoplasm of responding cells, thus terminating the direct effect of the endocannabinoids

FIGURE 2

Effects of anandamide and 2‐AG on various immune cells in a nutshell. Both anandamide and 2‐AG exert immunomodulatory roles on major immune cells such as T cells, B cells, natural killer cells, neutrophils, monocytes, macrophages, microglia, eosinophils, classical dendritic cells (cDC) and plasmacytoid dendritic cells (pDCs) as schematically represented. The choice of receptors on each cell varies depending on the specific effect of the endocannabinoid. CB1R, CB2R, GPR55, BLT1 and COX‐2 are already reported receptors for some of the effects (as shown over the arrowhead), while the receptors involved in the other effects remain to be identified