Modulation of the cannabinoid CB₂ receptor in microglial cells in response to inflammatory stimuli

Abstract

The cannabinoid system is known to be important in neuronal regulation, but is also capable of modulating immune function. Although the CNS resident microglial cells have been shown to express the CB 2 subtype of cannabinoid receptor during non-immune-mediated pathological conditions, little is known about the expression of the cannabinoid system during immune-mediated CNS pathology. To examine this question, we measured CB 2 receptor mRNA expression in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) and, by real-time PCR, found a 100-fold increase in CB 2 receptor mRNA expression during EAE onset. We next determined whether microglial cells specifically express the CB 2 receptor during EAE, and found that activated microglial cells expressed 10-fold more CB 2 receptor than microglia in the resting state. To determine the signals required for the up-regulation of the CB 2 receptor, we cultured microglial cells with combinations of c-interferon (IFN-c) and granulocyte) macrophage-colony stimulating factor (GM-CSF), which both promote microglial cell activation and are expressed in the CNS during EAE, and found that they synergized, resulting in an eight to 10-fold increase in the CB 2 receptor. We found no difference in the amount of the CB 2 receptor ligand, 2-arachidonylglycerol (2-AG), in the spinal cord during EAE. These data demonstrate that microglial cell activation is accompanied by CB 2 receptor up-regulation, suggesting that this receptor plays an important role in microglial cell function in the CNS during autoimmune-induced inflammation.

Cannabinoid CB1and CB2Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

“…In addition, Maresz et al (2005) have shown previously that CB 2 expression is upregulated in microglial cells in autoimmune-induced inflammation of the CNS in mice. Our results show that the distribution of these CB 2 -positive cells correlates with that of MHC-II-positive cells, whose localization and abundance are used as defining markers of plaque subtype (Trapp et al, 1999).…”

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

“…This pattern of CB2 expression in microglia has since been repeated in subsequent studies, and may have important implications for drugs targeting CB2 at various stages of microglial activation (see section 4). Most recently, Maresz et al [35] have demonstrated that the combination of IFN-and granulocyte mononuclear colony stimulating factor (GM-CSF) induces even higher levels of microglial CB2.…”

Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

“…In the central nervous system (CNS), MGL hydrolyzes 2-AG to arachidonic and glycerol, which plays an essential role in the regulation of endocannabinoid signaling (Scheme 1) [7]. An overexpression of MGL in the CNS has been associated with various neurological diseases because immoderate hydrolysis of 2-AG impairs the physiological roles of CB 1 and CB 2 [8,9]. These findings have motivated the development of MGL inhibitors, including a non-covalent inhibitor URB602 with low potency and selectivity for MGL [10] and irreversible covalent inhibitors such as 4-nitrophenyl-carbamate JZL184 [11], N-arachidonylmaleimide [12], and SAR629 [13].…”