CB₂ Cannabinoid Receptor Controls Myeloid Progenitor Trafficking: INVOLVEMENT IN THE PATHOGENESIS OF AN ANIMAL MODEL OF MULTIPLE SCLEROSIS

Cannabinoids are potential agents for the development of therapeutic strategies against multiple sclerosis. Here we analyzed the role of the peripheral CB₂ cannabinoid receptor in the control of myeloid progenitor cell trafficking toward the inflamed spinal cord and their contribution to microglial activation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). CB₂ receptor knock-out mice showed an exacerbated clinical score of the disease when compared with their wild-type littermates, and this occurred in concert with extended axonal loss, T-lymphocyte (CD4⁺) infiltration, and microglial (CD11b⁺) activation. Immature bone marrow-derived CD34⁺ myeloid progenitor cells, which play a role in neuroinflammatory pathologies, were shown to express CB₂ receptors and to be abundantly recruited toward the spinal cords of CB₂ knock-out EAE mice. Bone marrow-derived cell transfer experiments further evidenced the increased contribution of these cells to microglial replenishment in the spinal cords of CB₂-deficient animals. In line with these observations, selective pharmacological CB₂ activation markedly reduced EAE symptoms, axonal loss, and microglial activation. CB₂ receptor manipulation altered the expression pattern of different chemokines (CCL2, CCL3, CCL5) and their receptors (CCR1, CCR2), thus providing a mechanistic explanation for its role in myeloid progenitor recruitment during neuroinflammation. These findings demonstrate the protective role of CB₂ receptors in EAE pathology; provide evidence for a new site of CB₂ receptor action, namely the targeting of myeloid progenitor trafficking and its contribution to microglial activation; and support the potential use of non-psychoactive CB₂ agonists in therapeutic strategies for multiple sclerosis and other neuroinflammatory disorders.