Biochemistry and Molecular Biology I, Complutense
University, School of Biology, Madrid 28040.
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 towards 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 to 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 towards 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, 3, 5) and their receptors CCR1, 2), thus
providing a mechanistic explanation for its role in myeloid progenitor
recruitment during neuroinflamation. 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.
