Cannabinoid 1 receptor (CB1R) regulates the neuro-inflammatory and neurodegenerative damages of
experimental autoimmune encephalomyelitis (EAE) and of
multiple sclerosis (MS). The mechanism by which CB1R inhibition exerts inflammatory effects is still unclear. Here, we explored the cellular and molecular mechanisms of CB1R in the treatment of EAE by using a specific and selective CB1R antagonist
SR141716A. Our study demonstrated that
SR141716A accelerated the clinical onset and development of EAE, accompanied by
body weight loss.
SR141716A significantly up-regulated the expression of toll like receptor-4 (TLR-4) and
nuclear factor-kappaB/p65 (NF-κB/p65) on microglia/macrophages of EAE mice as well as levels of inflammatory factors (TNF-α, IL-1β, IL-6) and
chemokines (MCP-1, CX3CL1), accompanied by the shifts of
cytokines from Th2 (IL-4, IL-10) to Th1 (IFN-γ)/Th17 (IL-17) in the spinal cords of EAE mice. Similar changes happened on splenic mononuclear cells (MNCs) except
chemokine CX3CL1. Consistently,
SR141716A promoted BV-2 microglia to release inflammatory factors (TNF-α, IL-1β, IL-6) while inhibited the production of
IL-10 and
chemokines (MCP-1, CX3CL1). Furthermore, when splenic CD4+ T cells co-cultured with SR141716A-administered BV-2 microglia, the levels of
IL-4 and
IL-10 were decreased while production of
IL-17 and IFN-γ increased significantly. Our research indicated that inhibition of CB1R induced M1 phenotype-Th17 axis changed of microglia/macrophages through TLR-4 and NF-κB/p65 which accelerated the onset and development of EAE. Therefore, CB1R may be a promising target for the treatment of MS/EAE, but its complexity remains to be carefully considered and studied in further clinical application.