The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation

Abstract

Microglia, the resident immune cells of the brain, can take on a range of pro- or anti-inflammatory phenotypes to maintain homeostasis. However, the sustained activation of pro-inflammatory microglia can lead to a state of chronic neuroinflammation characterized by high concentrations of neurotoxic soluble factors throughout the brain. In healthy brains, the inflammatory processes cease and microglia transition to an anti-inflammatory phenotype, but failure to halt the pro-inflammatory processes is a characteristic of many neurological disorders. The endocannabinoid system has been identified as a promising therapeutic target for chronic neuroinflammation as there is evidence that synthetic and endogenously produced cannabinoids temper the pro-inflammatory response of microglia and may encourage a switch to an anti-inflammatory phenotype. Activation of cannabinoid type 2 (CB2) receptors has been proposed as the mechanism of action responsible for these effects. The abundance of components of the endocannabinoid system in microglia also change dynamically in response to several brain pathologies. This can impact the ability of microglia to synthesize and degrade endocannabinoids or react to endogenous and exogenous cannabinoids. Cannabinoid receptors also participate in the formation of receptor heteromers which influences their function specifically in cells that express both receptors, such as microglia. This creates opportunities for drug-drug interactions between CB2 receptor-targeted therapies and other classes of drugs. In this article, we review the roles of pro- and anti-inflammatory microglia in the development and resolution of neuroinflammation. We also discuss the fluctuations observed in the components of the endocannabinoid in microglia and examine the potential of CB2 receptors as a therapeutic target in this context.

Molecular Pathophysiological Mechanisms in Huntington’s Disease

“…Cannabinoid receptors (CBRs), a group of G-protein coupled receptors, have also important contributions. CB1 receptors were found abundantly expressed in striatal MSNs and exert neuroprotective effects via inducing expression of BDNF [ 315 ], while CB2 receptors, which regulate cell differentiation and survival as well as microglial polarization toward an M2 phenotype through the cyclic AMP protein kinase (PKA), extracellular signal-regulated kinase 1 (ERK1), JUN N-terminal kinases (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways, are expressed mainly in peripheral immune cells but seem a promising therapeutic target, because genetic ablations of these receptors in animal models exacerbated the motor and behavioral impairments [ 316 , 317 ], while administration of phytocannabinoids improved the motor impairments and attenuated neuronal loss in the striatum [ 318 ]. In addition, by interacting with the inositol-3-phosphate receptor 1 (IP3R1), by binding to the OMM, or by interacting with voltage-gated Ca 2+ channels and NMDARs, mHtt impairs the ability of mitochondria to handle increased Ca 2+ concentrations in microglia as well [ 319 ].…”

Microglial Endocannabinoid Signalling in AD

“…Microglia represent highly versatile cells that play a pivotal role in the neurobiological, neuroinflammatory and neurophysiological homeostasis of the CNS in both health and disease. Often referred to as brain-resident macrophages—a definition that has been often criticized due to the ontogenetic and functional differences between these two cell types—microglia maintain neuroinflammatory homeostasis by interacting with other immune cells (e.g., T cells) and by releasing a vast array of pro- and anti-inflammatory cytokines and endogenous lipids, such as eCBs, arachidonic acid-derived autacoids and pro-resolving mediators [ 12 , 13 , 14 ]; on the other hand, they also participate in pivotal brain functions, such as the elimination of dead neurons and cell debris [ 14 ], synapse pruning and, to a minor extent, the regulation of the synaptic neurotransmitter tone.…”

Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

“…Cannabinoids are well established as anti-inflammatory agents with a significant and wide range of immunosuppressive properties that have been meticulously reviewed before (20)(21)(22)(23)(24)(25). CBD, the nonpsychotic cannabinoid, was shown to induce myeloid-derived suppressor cells (MDSCs) which suppressed T cell proliferation in vitro and in vivo (26).…”