FcεRI/PLC axis promotes anandamide synthesis and the formation of CB2-GPR55 heteromers, modulating cytokine production in mast cells

Mast cells (MC) are crucial effectors in immediate allergic reactions. Monomeric IgE sensitizes MC and triggers various signaling responses. FcεRI/IgE/antigen crosslinking induces the release of several mediators, including bioactive lipids, but little is known about endocannabinoids (eCBs) secretion. Here, we studied the effects of IgE-induced sensitization and FcεRI crosslinking on anandamide (AEA) synthesis and release in bone marrow-derived mast cells (BMMC). Our results showed that mIgE induced AEA secretion through phospholipase C activation. Secreted AEA contributed to p38 phosphorylation induced by mIgE sensitization. Prolonged mIgE sensitization promoted the formation of long-lasting CB2-GPR55 heteromers. FcεRI crosslinking also caused AEA production. Notably, CB2 deficiency increased IL-2 and IL-3 cytokine expression in response to FcɛRI crosslinking. CB2 and GPR55 agonists reduced IL-2 and IL-3 mRNA expression caused by FcεRI activation. Our findings suggest that a) IgE binding to FcɛRI and its antigen-dependent activation leads to an AEA-dependent autocrine regulatory loop that contributes to intracellular signaling in MC and that b) CB2 and GPR55 receptors play a critical role in modulating the effector phase of MC activation by specifically regulating cytokine expression.