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(Journal of Leukocyte Biology. 2005;78:1192-1197.)
© 2005 by Society for Leukocyte Biology

Cannabinoid receptors in microglia of the central nervous system: immune functional relevance

G. A. Cabral1 and F. Marciano-Cabral

Department of Microbiology and Immunology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia

1 Correspondence: Department of Microbiology and Immunology, Virginia Commonwealth University, School of Medicine, 1101 E. Marshall Street, Richmond, VA 23298-0678. E-mail: gacabral{at}hsc.vcu.edu

ABSTRACT

Microglia, resident macrophages of the brain, function as immune effector and accessory cells. Paradoxically, they not only play a role in host defense and tissue repair but also have been implicated in a variety of neuropathological processes. Microglia, in addition to exhibiting phenotypic markers for macrophages, express CB1 and CB2 cannabinoid receptors. Recent studies suggest the existence of a third, yet-to-be cloned, non-CB1, non-CB2 cannabinoid receptor. These receptors appear to be functionally relevant within defined windows of microglial activation state and have been implicated as linked to cannabinoid modulation of chemokine and cytokine expression. The recognition that microglia express cannabinoid receptors and that their activation results in modulation of select cellular activities suggests that they may be amenable to therapeutic manipulation for ablating untoward inflammatory responses in the central nervous system.

Key Words: brain immune modulation • cytokines • marijuana • nitric oxide

Marijuana is a complex plant material, which can elicit a variety of pharmacological and immunological effects. Its major psychoactive component is {Delta}-9-tetrahydrocannabinol (THC), a compound that has been reported to account for the majority of effects on the immune system [1 , 2 ]. Several modes of action have been proposed as accounting for the effects of THC on immune cells. At high concentrations, such as those exceeding micromolar levels, THC and other cannabinoids may have direct effects on membranes, as they are highly lipophilic [3 ]. However, stereospecificity and structural requirements for biological activity indicate that cannabinoids also act through specific receptors. To date, two unique cannabinoid receptors have been identified. The CB1 is located primarily in the brain and is responsible for most, if not all, of the centrally mediated effects of cannabinoids [4 , 5 ]. The CB2 is present primarily in cells of the immune system but has been detected in adult human uterine tissue and embryonic organs and adult rat retina [6 , 7 ]. Both receptors are Gi/o protein-coupled, as evidenced by inhibition of adenylyl cyclase [8 ], inhibition of N-type calcium channels [9 ], and increased binding of nonhydrolyzable guanylyl-5'-O-({gamma}-thio)-triphosphate in the presence of cannabinoids [10 ]. The CB1 differs from the CB2, however, in that it also modulates Q-type calcium channels [11 ]. Recent studies suggest the existence of a third receptor, a non-CB1/non-CB2 receptor [12 13 14 ].

Major targets of marijuana and exogenous cannabinoids in the immune system are cells of macrophage lineage. Ultrastructural abnormalities have been observed in alveolar macrophages of humans who have been heavy users of marijuana [15 ] and in peritoneal macrophages of mice exposed in vitro to various concentrations of pure THC [16 ]. In addition, various functional defects of alveolar or peritoneal macrophages obtained from humans, rats, or mice following in vivo or in vitro exposure to marijuana or THC have been observed [17 ]. Microglia constitute a resident population of macrophages in the brain, the spinal cord, and retina and are morphologically, phenotypically, and functionally related to cells of macrophage lineage [18 19 20 21 ]. The function of quiescent microglia in normal brain is not well understood, but in pathological conditions, these cells play an active role as immunoeffector/accessory cells. Microglia migrate and proliferate during and after injury and inflammation [22 23 24 25 ]. Once activated, they produce various cytokines including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-{alpha} (TNF-{alpha}) and express major histocompatibility complex classes I and II antigens and the complement receptor, CR3. Microglia are also phagocytic and can process antigens and exert cytolytic functions. Paradoxically, these cells not only play a role in host defense and tissue repair in the central nervous system [26 , 27 ] but also have been implicated in nervous system disorders such as multiple sclerosis [28 ], Alzheimer’s disease [29 ], Parkinson’s disease [30 ], and AIDS dementia [31 32 33 ].

Microglia, as macrophage-like cells, undergo a process of maturation, differentiation, and activation, which is characterized by differential gene expression and correlative acquisition of specified functions [22 23 24 25 , 34 , 35 ]. This pattern of differential expression also applies to cannabinoid receptors (Fig. 1 ). Using an in vitro model of multistep activation, in which microglia are driven sequentially from a "resting" state to responsive, primed, and fully activated states, the CB1 was found at constitutive low levels at all states of cell activation. In contrast, the CB2 was found to be expressed inducibly and at maximal levels when microglia were in responsive and primed states. Collectively, the observations that expression of CB1 is constitutive, and that of the CB2 is inducible, that the two receptors are present at disparate levels, and that they exhibit distinctive compartmentalization [36 , 37 ] suggest that the two receptors have discriminative, functional relevance in microglia.



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  		Figure 1. Differential levels of CB2 mRNA are detected in neonatal rat brain cerebral cortex microglia in relation to cell activation state. (A) Southern blot of mutagenic reverse transcriptase-polymerase chain reaction (MRT-PCR) products from total nucleic acid of microglia maintained in medium ("responsive") or treated (6 h) with 100 U/ml rat interferon-{gamma} (IFN-{gamma}; "primed"), 100 U/ml rat IFN-{gamma} plus 100 ng/ml lipopolysaccharide (LPS; multisignal-activated), or 1 µg/ml LPS ("fully activated"). MRT-PCR was performed as described [36 ]. RT primers were used, which introduced a single base mismatch into the cDNA of CB1 or CB2 to generate a unique MspI or HindIII restriction site, respectively. The upper band of the doublet is amplified genomic DNA (gDNA). The lower band of the doublet (arrow) represents an amplified cDNA product from mRNA. (Upper panel) CB1 mRNA was detected at low levels for all treatment groups. (Lower panel) High levels of CB2 mRNA were detected for microglia maintained in medium or IFN-{gamma} (100 U/ml), and low levels were detected for cells treated with IFN-{gamma} plus LPS or with LPS alone. (B) Graphic representation of relative levels of CB2 mRNA depicted by MRT-PCR. The graph represents a single experiment performed in triplicate. The ordinate designated as Relative OD Units represents densitometric analysis of cDNA-amplified product based on area X pixel density and is represented relative to the corresponding densitometry obtained for the gDNA-amplified product. A significant decrease in levels of CB2 mRNA was recorded for cells treated with LPS or with LPS plus IFN-{gamma} as compared with those for untreated cells. Error bars are ± SD, n = 3, **, P< 0.01. OD, Optical density.

We have demonstrated that cannabinoids inhibit the production of inducible nitric oxide (iNO) by microglia, which are fully activated, in a mode that is mediated, at least in part, by the CB1 [36 ]. Table 1 lists select ligands, which have been used to study cannabinoid receptor-associated functions. Pretreatment of microglia with the CB1/CB2 high-affinity binding enantiomer CP55940 (Ki=0.9 nM) resulted in inhibition of iNO (Fig. 2 ) elicited in response to bacterial LPS used in combination with IFN-{gamma}. A less-inhibitory effect was exerted by the lower affinity-binding, paired enantiomer CP56667 (Ki=62 nM). The differential effect exerted by CP55940 versus CP56667 is consistent with a role of a cannabinoid receptor in the inhibition of iNO production, as selective binding affinity of paired cannabinoid stereoisomers has been shown to correlate with bioactivity in vivo and in vitro [5 ], and differential dose-related effects of one enantiomer versus its enantiomeric pair are implicative of a functional linkage to a receptor. The receptor, which was found as linked to the cannabinoid-mediated inhibition of iNO production, was CB1-based through the application of antagonist experiments. Treatment of microglia with the CB1-selective antagonist SR141716A prior to exposure to the agonist CP55940 blocked the CP55940-mediated inhibition of iNO production.


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  		Table 1. Properties of Select Cannabinoid Receptor Ligands



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  		Figure 2. CP55940-mediated inhibition of iNO release by microglia is blocked by the CB1 receptor-selective antagonist SR141716A. Microglia were pretreated (1 h) with 5 x 10–7 M SR141716A prior to exposure (8 h) to 5 x 10–6 M CP55940 or CP56667 and LPS plus IFN-{gamma} activation (24 h). Culture supernatants were assayed for nitrite using the Griess reagent. The CP55940 inhibition was stereoselective, as the paired enantiomer CP56667 was less bioactive. Results (mean±SEM of triplicate wells) are expressed as percent inhibition versus vehicle control (*, P<0.01, vs. SR141716A). Nitrite accumulation in LPS plus IFN-{gamma}-treated vehicle control cultures was 29.3 ± 3.5 (µM/106 cells). VEH, Vehicle (0.01% ethanol).

Cannabinoid-mediated alteration of microglial activities, as linked to the CB2, appears to be limited to that window of cell activation encompassing the responsive and primed states, for which the CB2 is expressed at high levels. Critical activities of responsive and primed microglia include chemotaxis and antigen processing/presentation, respectively. We have demonstrated that the partial agonist THC and the full agonist CP55940 inhibit the processing of select antigens by murine peritoneal macrophages and that this effect is mediated, at least in part, by the CB2 [47 , 48 ]. These observations suggest that a similar effect may occur for microglia. There is, however, accumulating evidence that the CB2 is expressed in vivo by microglia in the context of a variety of inflammatory states [49 ]. We have shown that Acanthamoeba culbertsoni (Fig. 3A ), an opportunistic, human pathogen, which is the causative agent of granulomatous amebic encephalitis (GAE) [50 ], can induce increased levels of CB2 in microglia in vitro (Fig. 3B) . Comparable results were obtained when total RNA from brain of mice inoculated with A. culbertsoni was assessed for CB2 mRNA (Fig. 3C) . Histopathological analysis of brain sections revealed focal brain lesions containing amebae circumscribed by cells exhibiting morphological features typical of microglia (Fig. 3D) . Collectively, these results, although not definitive, are consistent with microglia as the source of inducible expression of CB2 in vivo and suggest a potential target for ablating inflammation associated with GAE.



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  		Figure 3. Augmentation of CB2 mRNA levels in response to A. culbertsoni. (A) Scanning electron micrograph of an A. culbertsoni trophozoite. (B) Graphic representation of relative levels of cannabinoid receptor mRNA. Microglia were incubated with A. culbertsoni at a microglia:ameba ratio of 10:1. Levels of mRNA for the CB1 receptor remained unaffected, but those for the CB2 receptor exhibited a time-dependent augmentation as determined by RNase protection assay (RPA; PharMingen, San Diego, CA). The ordinate designated as Relative OD Units represents densitometric analysis based on area X pixel density relative to that of constitutively expressed L32 ribosomal (L32) mRNA product for each sample. The graph represents a representative single experiment. (C) RPA detection of mRNA for CB1 and CB2 receptors from whole brain homogenates of mice infected intranasally with A. culbertsoni (1x105 50% lethal dose). As expected, an excess of mRNA for the CB1 was obtained from whole brain homogenates. An apparent increase in levels of CB1 mRNA was noted for homogenates of brain obtained at 14 and 21 days. mRNA levels for the CB2 receptor exhibited a time-related increase following infection with amebae. Infection was confirmed by isolation of amebae in culture from mouse brains. (D) Hematoxylin and eosin-stained murine brain section demonstrating multiple foci of amebae surrounded by cells (arrows), which morphologically resemble microglia. (A, D) Original bars, 10 µm.

Recent studies suggest that a third, yet-to-be cloned receptor, a non-CB1, non-CB2 receptor [12 13 14 ], can also play a role in cannabinoid mediation of microglial activities. We have shown that the potent cannabinoid receptor agonist levonantradol (Ki=1.06 nM) inhibits the inducible expression of mRNAs for the proinflammatory cytokines IL-1{alpha} and TNF-{alpha} in a mode that is not blocked by the CB1 antagonist SR141716A or the CB2 antagonist SR144528 (Fig. 4 ). Similarly, the partial agonist THC (Ki=42 nM) and the agonist CP55940 (Ki=0.9 nM) inhibited the induction of cytokine mRNAs for IL-1{alpha}, IL-1ß, IL-6, and TNF-{alpha} in a mode that was not blocked by the CB1 or the CB2 antagonist (data not shown). Furthermore, enantiomeric selectivity for the CB1/CB2 high-affinity ligands, as compared with the paired, lower affinity counterparts, was not observed [51 ]. The "less bioactive" enantiomers CP56667 and HU211 exhibited inhibitory activity comparable with that of the potent CB1/CB2 agonists CP55940 and HU210, respectively. A similar outcome was obtained when the stereoisomers levonantradol (Ki=1.06 nM) and dextranantradol (Ki=3100 nM) were used. Collectively, the observations that gene expression for proinflammatory cytokines is associated with microglia that are fully activated and express low levels of CB2, that stereoselective paired cannabinoids exert comparable inhibitory effects on the induction of proinflammatory cytokine mRNAs, and that the CB1 and CB2 selective antagonists SR141716A and SR144528 do not block the inhibition of cytokine gene expression by the agonists CP55940 and levonantradol indicate that cannabinoid-mediated modulation of proinflammatory cytokine gene expression is not linked to the CB1 or the CB2. Whether these results are indicative of the presence of a non-CB1, non-CB2 receptor in microglia, which is functionally relevant when these cells are in a state of full activation, awaits biochemical and molecular analysis.



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  		Figure 4. The CB1 and CB2 receptor-specific antagonists do not block the inhibitory effects of levonantradol (Ki=1.06 nM) on cytokine mRNA expression. Microglia were treated (4 h) with levonantradol or pretreated (1 h) with 1 x 10–6 M SR141716A or SR144528 prior to exposure (3 h) to 1 x 10–6 M levonantradol. Cells then were treated (6 h) with LPS (100 ng/ml), and levels of cytokine mRNA were determined using the RiboQuant multiprobe RPA (PharMingen). The ordinate designates that the data are presented as the percent LPS-treated (100 ng/ml) vehicle control. Results are expressed as the mean percent cytokine mRNA expression of triplicate cultures versus that for the LPS-treated vehicle mean ± SEM (*, P<0.01; two-tailed Student’s t-test). SR1: CB1-selective antagonist SR141716A; SR2: CB2-selective antagonist SR144528; VEH: 0.01% ethanol.

In summary, microglia are macrophage-like cells that undergo a multistep process to full activation during inflammation. This multistep process is associated with differential gene expression and the acquisition of correlative functional activities. The differential expression of genes in relation to cell activation also applies to cannabinoid receptors. The CB1 is expressed constitutively and at low levels throughout multistep activation, indicating a potential for this receptor to be functionally relevant for a broad spectrum of cannabinoid-mediated effects. However, as it is expressed at low levels, it may exhibit less "sensitivity" to the action of nonselective CB1/CB2 agonists as compared with the CB2. In contrast, the CB2 is expressed inducibly and is present at high levels as compared with the CB1 when microglia are in responsive and primed states of activation. A signature, functional activity attributed to microglia, when in a responsive state, is chemotaxis, and these observations are consistent with reports of cannabinoid effects on cell migration, which is linked to the CB2 [52 ]. Recent pharmacological data suggest the existence of a third cannabinoid receptor, a non-CB1, non-CB2 receptor, which may play a role in cannabinoid-mediated inhibition of proinflammatory cytokine production, an activity that may be associated with microglia when fully activated.

ACKNOWLEDGEMENTS

This work was supported in part by National Institutes of Health/National Institute on Drug Abuse Awards R01 DA05832, R01 DA015608, and 2P50 DA05274.

Received April 24, 2005; revised August 19, 2005; accepted August 22, 2005.

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