Cannabinoids and the immune system: An overview

Abstract

Cannabinoids can influence the immune network. Data on the impact of exogenous cannabinoid ligands on immune function serve not only to understand how the endocannabinoid system modulates immune phenomena associated with infection or inflammation, but also to identify therapeutic targets for immune diseases. Cannabinoids can modulate immune reactions in the periphery but also in the brain, influence T cell subset balance and cytokine expression and play a role in the balance between neuroinflammation and neurodegeneration. Immune cells can synthesize endocannabinoids and also be influenced by cannabinoid analogues. Cannabinoid receptors show different expression on immune cells depending on activation status and stimuli. The complexity of relation between cannabinoid ligands of various classes and cannabinoid receptors brought the need to refine the simple conceptual frame of agonist–antagonists and offered potential implications for understanding interactions in pathological conditions. The immune influence of cannabinoid ligands is not fully elucidated. However, aspects of their immunomodulatory effects provide the basis for a context-dependent targeted therapeutic approach, thus leading to the possibility for the use of cannabinoids in the treatment of inflammatory disease.

Introduction

Cannabinoids, the biologically active constituents of marijuana, have been used for thousands of years for their psychoactive properties. The potential for marijuana to be both a therapeutic for a variety of conditions and a drug of abuse generated major efforts in order to clarify the biology and physiological role of cannabinoids in humans.

The marijuana plant contains more than 60 distinct chemical cannabinoids. Among them, D9-tetrahydrocannabinol (D9-THC) is the main psychoactive constituent, first structurally described in 1964 (Gaoni and Mechoulam, 1964) and giving the name for this class of compounds. In 1992, the first endogenous cannabinoid was isolated from porcine brain and identified as arachidonyl ethanolamide (anandamide; from the Sanskrit for “internal bliss”) (Devane et al., 1992). A second endocannabinoid was later identified (2-arachidonoyl glycerol) (Howlett et al., 2002). Since then, several synthetic cannabinoid analogues have been proven to induce similar in vivo effects such as analgesia and behavioral changes.

The study of the mechanism of action of cannabinoids led to the identification of a novel system of intercellular signaling, the endocannabinoid system. This system consists of endogenous ligands and receptors being subject to modulation by natural and synthetic cannabinoid agonists, and plays important modulatory functions in the brain and also in the periphery (Klein et al., 2003). The endocannabinoid system has been conserved during evolution. Binding sites with stereoselectivity were demonstrated in invertebrate microglia and immune cells (Salzet et al., 2000).

CB1R receptor is the most abundant G-protein-coupled receptor (GPCR) within the adult nervous system (Howlett et al., 2002). CB1R is localized to a number of functional brain structures, regulates synaptic neurotransmission and thus mediates psychoactive effects, and also providing a target for the use of cannabinoids as therapeutic agents for a number of neurological disorders (Croxford, 2003). CB2R receptor was described in 1993. It is not thought to be involved in psychoactive effects of cannabinoids and was initially found in the periphery, particularly in immune cells (mainly B cells and macrophages), but seems also to play a critical immune role in the CNS (Munro et al., 1993; Cabral et al., 2008).

The immunomodulatory and anti-inflammatory effects of cannabinoids are not fully elucidated. These effects have been reviewed over the years (Hollister, 1986; Cabral and Dove Pettit, 1998; Klein et al., 1998; Berdyshev et al., 2001; Roth et al., 2002; Croxford and Yamamura, 2005; Massi et al., 2006). Here, we review some aspects of the immune mechanisms affected by cannabinoids and, in this light, the therapeutic potential of these drugs in the treatment of immune diseases.