The CB2 receptor and its role as a regulator of inflammation

Abstract

The CB2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role. In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases. In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions. Herein, we review the pharmacology of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation. Finally, we discuss the possible therapies targeting the CB2 receptor and the questions that remain to be addressed to determine whether this receptor could be a potential target to treat inflammatory disease.

CB 1 and CB 2 Receptor Pharmacology

“…For an overview, please consult the following excellent reviews that have highlighted CB 1 signal transduction (Console-Bram, Marcu, & Abood, 2012; Howlett, 2005; Howlett et al, 2002; McAllister & Glass, 2002; Turu & Hunyady, 2010). The CB 2 receptor cellular signaling has been characterized as Gi/o-coupled signaling, although Gi/o inhibits cAMP production with varying efficacy depending upon experimental model and agonist used (reviewed in (Dhopeshwarkar & Mackie, 2014; Turcotte, Blanchet, Laviolette, & Flamand, 2016)). In addition to Gi/o-mediated signaling, CB 1 and CB 2 receptors are phosphorylated by G protein receptor kinases (GRKs) and subsequently associate with β-arrestin1 or β-arrestin2 (Breivogel et al, 2013; Chen et al, 2014), which can serve as a scaffold for interaction with proteins that divert signaling along β-arrestin-mediated pathways.…”

The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

“…The beneficial effects of THC explained with activation of cannabinoid receptors in diabetic rat pancreas . Turcotte et al . reported that the modulation of CB2 signalling may be promise for the treatment of various inflammatory conditions.…”

“…The beneficial effects of THC explained with activation of cannabinoid receptors in diabetic rat pancreas. [40] Turcotte et al [41] reported that the modulation of CB2 signalling may be promise for the treatment of various inflammatory conditions. Dai et al [42] suggested that the increased cannabinoid receptor expressions are correlated with the degree of fibrosis in chronic hepatitis B patients.…”

Interferon γ treatment increases endocannabinoid and related N‐acylethanolamine levels in T84 human colon carcinoma cells

“…Gut disorders such as Crohn's disease and ulcerative colitis have a strong inflammatory component, with cytokines such as IFNγ being involved in their pathogenesis (Groschwitz and Hogan, ). There is ample published evidence that immune responses can be modulated by ligands interacting with CB receptors, be they synthetic, plant‐derived or endogenous (see Tanasescu and Constantinescu, ; Kaplan, ; Turcotte et al, ). However, there is less information available with respect to the converse, that is, whether inflammatory cytokines affect endocannabinoid signalling, and most information concerns the effects of cytokines upon CB receptor expression (Maccarrone et al, ; Börner et al, ; Jean‐Gilles et al, ).…”