CB2 Receptor in Microglia: The Guardian of Self-Control

Abstract

Microglia are key to maintaining the homeostasis of the brain. These immune cells of the brain can be our biggest ally in fighting infections, but can worsen pathology or hinder recovery when uncontrolled. Thus, understanding how microglia contribute to neuroinflammatory processes and how their activity can be controlled is of great importance. It is known that activation of endocannabinoid system, and especially the cannabinoid type 2 receptor (CB2R), decreases inflammation. Alongside its non-psychoactive effect, it makes the CB2R receptor a perfect target for treating diseases accompanied by neuroinflammation including neurodegenerative diseases. However, the exact mechanisms by which CB2R regulates microglial activity are not yet understood. Here, we review the current knowledge on the roles of microglial CB2R from in vitro and in vivo studies. We look into CB2R function under physiological and pathological conditions and focus on four different disease models representing chronic and acute inflammation. We highlight open questions and controversies and provide an update on the latest discoveries that were enabled by the development of novel technologies. Also, we discuss the recent findings on the role of microglia CB2R in cognition and its role in neuron–microglia communication.

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

“…Moreover, selective CB2R agonists were successfully used to suppress inflammatory and neuropathic pain without psychotropic side effects caused by the use of THC or other CB1R-related pharmaceuticals [ 35 , 36 ]. The overexpression of CB2R receptors was correlated with microglial polarisation from a pro-inflammatory M1 to anti-inflammatory M2 state by a yet not fully elucidated mechanism [ 37 ]. Thus, CB2R are regarded as a highly valuable marker for the early detection and treatment of several neuropathological conditions [ 38 , 39 ].…”

Cannabinoid Receptor 2 Alters Social Memory and Microglial Activity in an Age-Dependent Manner

“…CB 2 R expression is increased in microglia and macrophages in many diseases and acute inflammatory states, but also during aging, which may be due to inflammaging [ 41 , 42 ]. Aged microglia frequently have dystrophic morphology, with increased pro-inflammatory and decreased neuroprotective functions [ 33 , 43 , 44 , 45 ].…”

Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

“…There is interest in the potential of targeting cannabinoid receptors for combating a variety of diseases. Despite targeting the CB 1 R was the main objective in cannabinoid-related drug discovery, the psychotropic action of some cannabinoids acting on its receptors and the side effects of a CB 1 R antagonist approved to combat obesity, rimonabant, has shifted the focus toward the CB 2 R. The limited expression of the CB 2 R in some CNS regions and its upregulation in activated glial cells have led to propose this receptor as target to limit neuroinflammation, to limit neurotoxicity induced by oxidative stress, to afford neuroprotection and/or the increase neurogenesis/gliogenesis [11,[35][36][37][38][39][40][41]. Medications targeting cannabinoid receptors have been approved for a very limited therapeutic interventions (Sativex ® , Marinol ® , Epidiolex ® ; mainly to combat spasticity and emesis).…”