Targeting cannabinoid signaling in the immune system: “High”-ly exciting questions, possibilities and challenges

It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the“phytocannabinoids” [pCB; e.g., (−)-trans-Δ9-tetrahydrocannabinol (THC), (−)-cannabidiol,etc.] can influence a wide array of biological processes, and the human body isable to produce endogenous analogs of these substances [“endocannabinoids” (eCB),e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG),etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoidreceptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesisand degradation of the ligands constitute the endocannabinoid system (ECS),a recently emerging regulator of several physiological processes. The ECS is widelyexpressed in the human body, including several members of the innate and adaptiveimmune system, where eCBs, as well as several pCBs were shown to deeply influenceimmune functions thereby regulating inflammation, autoimmunity, antitumor, as wellas antipathogen immune responses, etc. Based on this knowledge, many in vitro andin vivo studies aimed at exploiting the putative therapeutic potential of cannabinoidsignaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organtransplantation, and to dissect the complex immunological effects of medical and“recreational” marijuana consumption. Thus, the objective of the current article is (i) tosummarize the most recent findings of the field; (ii) to highlight the putative therapeuticpotential of targeting cannabinoid signaling; (iii) to identify open questions and keychallenges; and (iv) to suggest promising future directions for cannabinoid-based drugdevelopment