Role endocannabinoid-CB₂ signaling in various diseases affecting humans. Selected disease conditions are shown in which dysregulation of the endocannabinoid-CB₂ signaling is implicated in the pathology. Conversely, in these conditions pharmacological modulation of CB₂ receptors may represent a novel therapeutically exploitable strategy.

Cannabinoid 2 receptor (CB₂) expression and its known cellular functions. CB₂ receptors are most abundantly expressed in cells of the immune system and in cells of immune origin. In these cells CB₂ receptors mostly mediate immunosuppressive effects. CB₂ receptor expression was also reported in activated/diseased various other cell types. Importantly, in various pathological conditions CB₂ receptors were reported to be markedly upregulated in most of the shown cell types, and were attributed to play important role in various indicated cellular functions. Some of these effects are context dependent and may largely be determined by the type of the injury/inflammation and its stage.

Therapeutic targets of cannabinoid 2 receptor (CB₂) modulation in inflammation and tissue injury. Endothelial cell activation and endothelial dysfunction is an early event inflicted by any kind of tissue injury/insult. Activated endothelial cells release various pro-inflammatory chemokines (e.g. monocyte chemoattractant protein 1 (MCP-1/CCL2), chemokine (C-C motif) ligand 5/Regulated on Activation Normal T Cell Expressed and Secreted (also CCL5/RANTES), macrophage inflammatory proteins (e.g. MIP-1α/CCL3, MIP-2/CXCL2s), etc.), which attract inflammatory cells to the site of injury. Activated endothelial cells increase the expression and also release soluble adhesion molecules such as vascular adhesion molecule 1 (VCAM-1/CD106), intercellular adhesion molecule 1 (ICAM-1/CD54), which facilitated the attachment of inflammatory cells. This is followed by transmigration of inflammatory cells through the damaged endothelium and attachment to the parenchyma cells and activation (e.g. release of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), IL-6, IF-γ, etc.), chemokines (CCL2, CCL5, CCL3, and CXCL2), reactive oxygen and nitrogen species (ROS/RNS), as well as various factors which promote matrix/tissue remodeling (e.g. matrix metalloproteinases (MMPs), TGF-β, etc.). The pathological remodeling is further facilitated by ROS/RNS- and inflammatory mediators-induced activation of vascular smooth muscle cells and fibroblasts leading to their increased proliferation and release of various profibrotic and other pro-inflammatory mediators. The initial phase of inflammation may largely depend on the pathological condition (e.g. during the ischemia/reperfusion injury the initial players are predominantly neutrophils, while in early atherosclerosis mostly monocytes/macrophages) and the presence of residual inflammatory-derived cells (e.g. Kupffer cells in the liver, microglia in the brain, etc.), but later most inflammatory cells are present at various degree. CB₂ receptor agonists (or in certain cases as discussed in this review the inverse agonist) protect against inflammation and tissue injury by attenuating endothelial cell activation/inflammatory response, chemotaxis of inflammatory cells, rolling and adhesion of inflammatory cells to the endothelium, transendothelial migration, adhesion to the parenchymal cells and activation (release of pro-inflammatory cytokines, chemokines, ROS/RNS, MMPs, etc.) and fibrosis.