Cannabinoid receptor 2 agonists inhibit migration of activated dendritic cells via modulation of MMP-9 (173.23)

In murine models of multiple sclerosis (experimental autoimmune encephalomyelitis or EAE), cannabinoid receptor 2 (CB2) agonists have been shown to be beneficial, reducing the number of CNS infiltrating leukocytes. Adhesion molecules, chemokines, and matrix metalloproteinases (MMPs), particularly MMP-9, play important roles in migration to the CNS. Antigen presenting cells such as dendritic cells (DC) and macrophages, as well as activated microglia are major producers of MMP-9. In this study, we investigated the effects of CB2 receptor agonists on DC migration and MMP-9 production utilizing both in vitro and in vivo migration assays. DC activated with cytokine cocktail (TNFα+IL-1β+IL-6+PGE2) in the presence or absence of CB2R agonist exhibited similar migratory capacity in transwell migration assays. However, the CB2R agonist treated cells migrated less in matrigel migration assays as compared to untreated cells. We found that this effect was due to reduced MMP-9 production in CB2R agonist treated cells. Also, in the in vivo migration assay using cytokine cocktail-activated DCs injected into mice footpads, we found significantly fewer CB2R agonist-treated DCs in the draining lymph nodes. Our data indicate that one of the mechanisms by which CB2R agonists attenuate inflammation is the inhibition of MMP-9 release which results in decreased migration of activated dendritic cells.