<scp> S1P ₃ </scp> Receptor Mediates the Proinflammatory Effect of the Endocannabinoid 2‐Arachidonoylglycerol in Endometriotic Epithelial Cells

Endometriosis is a chronic inflammatory disease characterized by the ectopic implantation of endometrium outside the uterus associated with pelvic pain and infertility. The molecular mechanisms involved in the pathogenesis of endometriosis are complex and far from being fully elucidated. We recently showed that the signaling of the bioactive sphingolipid sphingosine 1-phosphate (S1P) is deeply dysregulated in endometriosis. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), via ligation to G-protein coupled receptors, CB1, CB2, and GPR18 as well as the cation channel TRPV1, play a crucial role in the modulation of pain and inflammation. Here, the role of endocannabinoid signaling in endometriosis and its possible cross talk with the S1P signaling axis has been investigated. It has been found that CB1, CB2, GPR18, TRPV1 as well as the enzymes involved in endocannabinoid metabolism are expressed in endometriotic lesions. Furthermore, the effect of 2-AG and AEA in the modulation of inflammation has been established in human endometriotic epithelial cells. 2-AG, but not methanandamide (MAEA), the nonhydrolyzable AEA analogue, induced a marked increase in the expression of cyclooxygenase 2 and various pro-inflammatory interleukins (IL-1β, IL-6 and IL-8). Interestingly, S1P₃, whose expression is augmented by 2-AG, is crucial for transducing the biological action of the endocannabinoid. Indeed, S1P₃ pharmacological blockade or its specific silencing impaired the pro-inflammatory action of 2-AG. In conclusion, these findings demonstrate, for the first time, the occurrence of a functional interplay between endocannabinoids and S1P signaling in endometriosis, paving the way for novel pharmacological strategies to treat the disease.