Endocannabinoid signaling in microglial cells

Abstract

The endocannabinoid signaling system (eCBSS) is composed of cannabinoid (CB) receptors, their endogenous ligands (the endocannabinoids, eCB) and the enzymes that produce and inactivate these ligands. Neurons use this signaling system to communicate with each other and Delta9-tetrahydrocannabinol (THC), the main psychotropic ingredient of Cannabis sativa, induces profound behavioral effects by impinging on this communication. Evidence now shows that microglia, the macrophages of the brain, also express a functional eCBSS and that activation of CB receptors expressed by activated microglia controls their immune-related functions. This review summarizes this evidence, discusses how microglia might use the eCBSS to communicate with each other and neighboring cells, and argues that compounds selectively targeting the eCBSS expressed by microglia constitute valuable therapeutics to manage acute and chronic neuroinflammation, without inducing the psychotropic effects and underlying addictive properties commonly associated with THC.

Figure 1. Endocannabinoid signaling in healthy brain

(a) CB₁ receptors are expressed by neurons and CB₂ receptors by peripheral immune cells. (b) Neuronal depolarization and neurotransmitter release (e.g. glutamate, Glu) leads to post-synaptic rise in calcium, which increases endocannabinoid (eCB) production. eCB act as retrograde signals onto presynaptic CB₁ receptors, reducing neurotransmitter release. (c) Δ⁹-tetrahydrocannabinol (THC) acts as a high-affinity partial agonist at CB₁ receptors, impinging on this eCB signaling.

Figure 2. Endocannabinoid signaling in diseased brain

(a) Neurons damaged by injury, toxins or pathogens release large amounts of Glu, (b) resulting in strong neuronal depolarization and Glu receptor activation and sustained rise in post-synaptic calcium and enhanced eCB production. CB₁ receptor expression is up-regulated in damaged neurons. eCB acting at pre-synaptic CB₁ receptors reduce neurotransmitter release and at post-synaptic CB₁ receptors increase Erk activity and allied gene expression (e.g. BDNF). (c) ATP, released from damaged cells, stimulates purinergic receptors expressed by astrocytes and enhances eCB production, which may participate in stimulating pre- and post-synaptic CB₁ receptors. (d) Neuronal damage is associated with microglial cell activation (M₁, proinflammatory phenotypes), resulting in free radicals and toxin release, as well as up-regulation of CB₂ receptor expression. (e) eCB produced by damaged neurons and stimulated astrocytes act on CB₂ receptors expressed by microglial cells, (f) leading to a switch in their phenotype (M₂, anti-inflammatory phenotype) and further up-regulation of CB₂ and P2X₇ receptor expression. (g) ATP released by damaged cell enhances the abundant and sustained production of eCB from microglia, which participates in stimulating pre- and post-synaptic CB₁ receptors, (h) as well as in recruiting peripheral monocytes/macrophages (in concert with the chemokine MCP-1 and the cytokine TNFα). The overall result is to limit the propagation of cell damage and favor cell repair (e.g. through the release of BDNF).