Crosstalk between endocannabinoid and immune systems: a potential dysregulation in depression?

Abstract

Background: The endocannabinoid (eCB) system, an endogenous lipid signaling system, appears to be dysregulated in depression. The role of endocannabinoids (eCBs) as potent immunomodulators, together with the accumulating support for a chronic low-grade inflammatory profile in depression, suggests a compelling hypothesis for a fundamental impairment in their intercommunication, in depression.

Objective: We aim to review previous literature on individual associations between the immune and eCB systems and depression. It will focus on peripheral and central mechanisms of crosstalk between the eCB and immune systems. A potential dysregulation in this crosstalk will be discussed in the context of depression.

Results: Investigations largely report a hypoactivity of the eCB system and increased inflammatory markers in individuals with depression. Findings depict a multifaceted communication whereby immunocompetent and eCB-related cells can both influence the suppression and enhancement of the other's activity in both the periphery and central nervous system. A dysregulation of the eCB system, as seen in depression, appears to be associated with central and peripheral concentrations of inflammatory agents implicated in the pathophysiology of this illness.

Conclusion: The eCB and immune systems have been individually associated with and implicated in pathogenic mechanisms of depression. Both systems tightly regulate the other's activity. As such, a dysregulation in this crosstalk has potential to influence the onset and maintenance of this neuropsychiatric illness. However, few studies have investigated both systems and depression conjointly. This review highlights the demand to consider joint eCB-immune interactions in the pathoetiology of depression.

Keywords: 2-AG; Anandamide; CNS; Cytokine; Eicosanoids; Inflammation; Lymphocyte; Microglia; Microglial polarisation; Prostaglandin.

Fig. 1

AEA and 2-AG are synthesised from enzymes, NAPE-PLD and DAGL, respectively, from glycerophospholipids in the phospholipid bilayer of the cellular membrane. Both eCBs bind to intracellular and extracellular CB1R and CB2R. Intracellular degradation of AEA and 2-AG occurs when bound to FAAH and MAGL, respectively. Products of this are AA and either glycerol, from 2-AG, or ethanolamine, from AEA

Fig. 2

Eicosanoids, PGEs and leukotrienes, can be metabolised from two differential eCB-related pathways. 2-AG and AEA can be metabolised directly into either PGEs or leukotrienes by COX and LOX, respectively. Alternatively, degradation of eCBs can occur via enzymes, either MAGL or FAAH, into AA, which is subsequently oxidised by COX and LOX to produce PGEs and leukotrienes, respectively. Therefore, fluctuations in eCB concentration can influence eicosanoid levels

Fig. 3

Differential expression of CB1R and CB2R on the luminal and abluminal membranes, respectively, may lead to unidirectional transport of AEA. CB1R increases nitric oxide (NO) production, which in turn induces activity of a selective AEA membrane transporter (AMT). Increased levels of AEA are then transported across the BBB. CB2R negates NO production and therefore suppresses AMT activity. Thus, transport of abluminal AEA across the BBB is reduced

Fig. 4

Differential binding of 2-AG to CBRs on microglia elicits differential immunomodulatory effects, dependent on the state of microglial activation. Binding of CB2R on M2 state microglia is associated with increased concentrations of anti-inflammatory agents. CB2R-2AG binding inhibits IFN-γ-induced microglial cell expression of proinflammatory agents. 2-AG binding to CB1R in M1-activated state microglia, results in increased pro-inflammatory mediators

Fig. 5

Peripheral: eCB action on CB2Rs results in suppression of immune cell activation by inhibiting AC conversion of adenosine tri-phosphate (ATP) to cAMP. eCBs can be metabolised in to arachidonic acid (AA) which can subsequently be converted to inflammatory molecule, prostaglandins (PGE), or anti-inflammatory agent, leukotrienes (LOX) CNS: 2-AG induces M2-state microglia to secrete anti-inflammatory agents; BDNF, LXA4 and IL-10, mediated by CB2Rs