CB2 receptors in the brain: role in central immune function

G A Cabral, E S Raborn, L Griffin, J Dennis, F Marciano-Cabral, G A Cabral, E S Raborn, L Griffin, J Dennis, F Marciano-Cabral

Abstract

Recently, it has been recognized that the cannabinoid receptor CB2 may play a functionally relevant role in the central nervous system (CNS). This role is mediated primarily through microglia, a resident population of cells in the CNS that is morphologically, phenotypically, and functionally related to macrophages. These cells also express the cannabinoid receptor CB1. The CB1 receptor (CB1R) is constitutively expressed at low levels while the CB2 receptor (CB2R) is expressed at higher levels and is modulated in relation to cell activation state. The relatively high levels of the CB2R correspond with microglia being in 'responsive' and 'primed' states, suggesting the existence of a 'window' of functional relevance during which activation of the CB2R modulates microglial activities. Signature activities of 'responsive' and 'primed' microglia are chemotaxis and antigen processing, respectively. The endocannabinoid 2-arachidonylglycerol has been reported to stimulate a chemotactic response from these cells through the CB2R. In contrast, we have shown in vivo and in vitro that the exogenous cannabinoids delta-9-tetrahydrocannabinol and CP55940 inhibit the chemotactic response of microglia to Acanthamoeba culbertsoni, an opportunistic pathogen that is the causative agent of Granulomatous Amoebic Encephalitis, through activation of the CB2R. It is postulated that these exogenous cannabinoids superimpose an inhibitory effect on pro-chemotactic endocannabinoids that are elicited in response to Acanthamoeba. Furthermore, the collective results suggest that the CB2R plays a critical immune functional role in the CNS.

Figures

Figure 1
Figure 1
In vitro model of macrophage/microglial multi-step activation. Peritoneal macrophages, macrophage-like cells and microglia can be driven sequentially in response to multiple signals from ‘resting' to ‘responsive', ‘primed' and ‘fully' activated states, a process that mimics events in vivo. Each of these states is characterized by differential gene expression and acquisition of correlative distinctive functional capabilities (modified from: Adams and Hamilton, 1984; Hamilton et al., 1986; Hamilton and Adams, 1987).
Figure 2
Figure 2
THC downregulates accumulation of macrophage-like cells at focal sites of Acanthamoeba in mouse brain. (B6C3)F1 mice were treated once intraperitoneally with THC (25 mg kg−1) or vehicle (ethanol:emulphor:saline, 1:1:18), inoculated intranasally with 3 LD50 of A. culbertsoni, killed and the brains were removed. Paraffin sections were stained with haematoxylin and eosin. (a) Section from vehicle-treated mouse depicting accumulation of macrophage-like cells around Acanthamoeba (arrow). (b) Section from THC-treated mouse depicting Acanthamoeba in the brain in the absence of macrophage-like cell accumulation (arrows). THC, delta-9-tetrahydrocannabinol.
Figure 3
Figure 3
THC and CP55940 inhibit chemotaxis of microglia. Microglia were isolated from neonatal Sprague–Dawley rats and purified as described (Waksman et al., 1999), treated (3 h) with cannabinoid or vehicle (0.01% ethanol) and assessed (2 h) for migration against CM. The CB1R/CB2R partial agonist THC has a Ki=46 nM at the CB2R, while the potent full agonist CP55940 has a Ki=0.9 nM at the CB2R. *P<0.05, **P<0.01, ***P<0.001. n=3/group. CB1R, CB1 receptor; CB2R, CB2 receptor; CM, Acanthamoeba-conditioned medium; THC, delta-9-tetrahydrocannabinol.
Figure 4
Figure 4
The CB2R, but not the CB1R, agonist inhibits chemotaxis of microglia. Microglia were treated (3 h) with cannabinoid or vehicle (0.01% ethanol) and assessed (2 h) for migration against CM. O2137: CB1R Ki=2700 nM, CB2R Ki=11 nM; ACEA CB1R Ki=1.4 nM, >1400-fold selectivity over the CB2R. *P<0.05. n=3 per group. ACEA, (N-(2-Chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide; CB1R, CB1 receptor; CB2R, CB2 receptor; CM, amoeba-conditioned medium.
Figure 5
Figure 5
The CB2R antagonist reverses CP55940-mediated inhibition of chemotaxis of microglia. Microglia were treated (1 h) with antagonist (10−6 M) or vehicle (VEH), treated (30 min) with CP55940 or vehicle and assessed (2 h) for migration against CM. *P<0.05, **P<0.01. n=3 per group. CB2R, CB2 receptor; CM, amoeba-conditioned medium.
Figure 6
Figure 6
Model of role of CB2R in modulation of microglial chemotactic response to Acanthamoeba. Acanthamoeba elicit proteases, phospholipases and other factors that serve to generate cleavage products of phospholipids in microglial membranes through the action of phospholipases. It is postulated that bioactive lipid mediators thus generated include the endocannabinoid 2-AG that serves to drive chemotaxis of microglia by autocrine and/or paracrine activation of the CB2R. The exogenous cannabinoid THC may inhibit this chemotactic response by superimposing its effect on 2-AG by inhibiting its synthesis and/or release or by exerting a relatively long-lasting ligation to the CB2R. 2-AG, 2-arachidonylglycerol; CB2R, CB2 receptor; THC, delta-9-tetrahydrocannabinol.

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