Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease

Abstract

The impact of the endogenous cannabinoids (AEA, 2-AG, PEA, and virodamine) on the immune cell expressed cannabinoid receptors (CB1, CB2, TRPV-1, and GPR55) and consequent regulation of immune function is an exciting area of research with potential implications in the prevention and treatment of inflammatory and autoimmune diseases. Despite significant advances in understanding the mechanisms through which cannabinoids regulate immune functions, not much is known about the role of endocannabinoids in the pathogenesis or prevention of autoimmune diseases. Inasmuch as CB2 expression on immune cells and its role has been widely reported, the importance of CB1 in immunological disorders has often been overlooked especially because it is not highly expressed on naive immune cells. Therefore, the current review aims at delineating the effect of endocannabinoids on CB1 receptors in T cell driven autoimmune diseases. This review will also highlight some autoimmune diseases in which there is evidence indicating a role for endocannabinoids in the regulation of autoimmune pathogenesis. Overall, based on the evidence presented using the endocannabinoids, specifically AEA, we propose that the peripheral CB1 receptor is involved in the regulation and amelioration of inflammation associated with autoimmune diseases.

Transient Retinal Dysfunctions after Acute Cannabis Use

“…Additionally, there is growing evidence that cannabis and exocannabinoids exhibit immunoregulatory properties through the activation of cannabinoid receptors [17,18] . Especially, endocannabinoids are known to exert immune functions by modulating cytokine release and an involvement of the cannabinoid system in a protective general mechanism may occur in specific immunological conditions to decrease the immune response [19,20] . Under pathological conditions such as lupus erythematosus, the expression of cannabinoid receptors may be enhanced and they could play neuroprotective and immunosuppressive roles [21] .…”

Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

“…Nearly 30 years after the discovery of THC, two G-coupled protein receptors, identified as cannabinoid receptor 1 (CB1) and 2 (CB2), were discovered with other less studied cannabinoid receptors discovered in the ensuing years (Matsuda et al 1990; Munro et al 1993). CB1 is predominantly expressed in the CNS but is also present on activated immune cells, albeit to a lesser degree (Sido et al 2014). In contrast, CB2 is most prominently expressed on the cells of the immune system and activation of CB2 can lead to significant alterations in the immune response including apoptosis, cytokine suppression, altered T cell differentiation towards T regulatory (Treg) cells, induction of Myeloid-Derived Suppressor Cells (MDSCs) and a shift of the immunological status from a proinflammatory (Th1) to an antiinflammatory (Th2) profile (McKallip et al 2002; Klegeris et al 2003; Do et al 2004; Lombard et al 2007; Hegde et al 2008; Nagarkatti et al 2009; Nagarkatti et al 2010; Singh et al 2012b; Sido et al 2014).…”

“…In the CNS the endocannabinoid system is associated with the regulation of motor control, memory, cognitive processes, and neurotransmitter release (Mackie 2008; Pertwee 2008; Kano et al 2009). While it was originally believed that the endocannabinoid system was limited to the central nervous system, it is now known that the immune and reproductive systems also express cannabinoid receptors and are thus impacted by cannabinoids (Smita et al 2007; Nagarkatti et al 2009; Pandey et al 2009a; Rieder et al 2010; Sido et al 2014). Indeed, endocannabinoids play an integral role in autoimmune diseases, with CB1 specifically involved in the regulation and amelioration of autoimmune induced inflammation (Sido et al 2014).…”

“…AEA is an endocannabinoid that acts on the same receptors (CB1 and CB2) as exogenous cannabinoids such as THC (Sido et al 2014). AEA is most concentrated in the CNS but is also present in the periphery.…”

Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed‐type hypersensitivity

“…The EC system is well known to play a role in immune response (as reviewed throughout the years by ). Moreover, CB receptor agonists such as Δ‐9‐tetrahydrocannabinol (THC), AEA, and 2‐AG have all been connected to the regulation of lymphocyte activation.…”