Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

Abstract

It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−)-trans-Δ9-tetrahydrocannabinol (THC), (−)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able 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 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.

Crosstalk Between the Gut Microbiome and Bioactive Lipids: Therapeutic Targets in Cognitive Frailty

“…The eCB system also includes their analogs: Oarachidonoylethanolamine, N-oleoylethanolamine (OEA), and N-palmitoylethanolamine (PEA) (60,61,93). These analogs are produced by most tissues and immune cells via a set of specific synthetizing enzymes, N-acylphosphatidylethanolaminehydrolyzing phospholipase D (NAPE-PLD), which synthetizes AEA, and diacylglycerol lipase (DAGL), which synthetizes 2-AG.…”

“…These analogs are produced by most tissues and immune cells via a set of specific synthetizing enzymes, N-acylphosphatidylethanolaminehydrolyzing phospholipase D (NAPE-PLD), which synthetizes AEA, and diacylglycerol lipase (DAGL), which synthetizes 2-AG. In turn, AEA is degraded by the fatty acid amide hydrolase (FAAH), while 2-AG is degraded by monoacylglycerol lipase (MAGL) (41,93). These analogs enhance the effect of the endogenous eCB (i.e., AEA and 2-AG) by inhibiting their inactivation (60).…”

“…Physiologically, these molecular targets are present on nerve terminals of extrinsic primary afferents (TRPV1) and on the enteric nervous system and enterocytes (PPARα, GPR55) (93). They act "on demand" in the regulation of gastrointestinal motility, secretion, and the maintenance of the epithelial barrier integrity (60,93,95), and, critically, their imbalance is associated with several gastrointestinal diseases such as bowel inflammation and colon cancer (60,93,95).…”

“…This process leads to leakage of gram-negative bacterial components, which elevates the plasmatic levels of LPS (i.e., metabolic endotoxemia), exacerbating the pro-inflammatory actions that are associated with the onset of several metabolic, inflammatory, and neurodegenerative disorders (60,98). Due to the high abundance of the eCB receptors and enzymes in the central and peripheral nervous system, these mediators can rapidly react to disturbances in the gut to maintain homeostasis according to its physiological needs, functioning to reduce pain and to alleviate gastroenteric, neurodegenerative, and inflammatory damage (61,92,93). Thus, targeting the eCB system may be a promising therapeutic strategy to modulate the microbiome, the gut-brain axis, and potentially, cognitive frailty.…”

Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence

“…T he endogenous cannabinoid signaling system (ECS) is a highly conserved, ubiquitous, pleiotropic biochemical system known as a gatekeeper in immune homeostasis. 1 A multitude of ECS-mediated immunosuppressive effects have been demonstrated to date, including inhibition of immune cell proliferation, migration and antibody production, induction of apoptosis, and cytokine suppression (via downregulation of immunoregulatory genes). Given these effects, are phytocannabinoids helpful or harmful for immune competency in the context of the current coronavirus disease 2019 (COVID-19) pandemic?…”