Efficacy of cannabidiol treatment in experimental MS is due to immunosuppressive activity of myeloid cells in CNS downregulating recruitment of CD4+ T cells, proinflammatory chemokines and gasdermin D expression

Abstract

Abstract Cannabidiol (CBD) is a nonpsychoactive ingredient from Cannabis that has garnered attention in the medical community due to its anti-inflammatory properties and therapeutic potential. CBD has in particular become a popular alternative medicine among individuals with autoimmune disorders due to CBD lacking the side effects and costs associated with immunosuppressants. To better define how CBD inhibits inflammation, we studied the effects of orally administering CBD (20mg/kg) in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Using single cell RNA sequencing on cells isolated from the central nervous system (CNS) of EAE mice, we demonstrated that CBD treatment inhibits neuroinflammation by regulating gene expression and infiltration of myeloid cells. Within the resident and infiltrating myeloid cells of the CNS, there was decreased expression of inflammatory cytokines and chemokines (CXCL9, CXCL10, IL-18) associated with neuroinflammation and CD4+ T cell recruitment, pyroptosis initiators (gasdermin D; Gsdmd), oxide synthesizers (Arg1) and antigen presentation mediators (CD40) in CBD-treatment group. Additionally, CBD yielded an increase in the polymorphonuclear myeloid derived suppressor cells in the CNS, signifying immunotolerance induction at the site of inflammation. In the VEH treated mice, we found CD4+ T cells that express the receptor for IL-18 (IL-18r1) that are absent in CBD treated mice, suggesting CBD affects T cell activity via inhibition of myeloid cell activity. This data shows that CBD treatment ameliorates EAE by inhibiting infiltration, pro-inflammatory cytokine production, antigen presentation, T cell recruitment and pyroptosis of myeloid cells in the CNS.