Cannabinoids attenuate the severity of colitis in a murine model and modulate CXCR4 expression

Chemokines are small cytokines that govern leukocyte migration. Among various chemokines, the expression of CXCR4 and its cognate ligand have been shown to increase in the progression of several inflammatory conditions, including inflammatory bowel diseases (IBDs). Some studies demonstrated that cannabinoids exhibit immunosuppressive properties that include modulation of immune cell migration. In the present study, we examined whether cannabinoids regulate the inflammatory response, in part, by modulating chemokine-mediated leukocyte infiltration into inflamed tissue of the gastrointestinal tract in colitis. In the present study we evaluated the effect of cannabis extract and synthetic cannabinoids on the expression of CXCR4 on mouse splenocyte as well as human PBMC stimulated with LPS. Activation related CXCR4 upregulation was attenuated by several cannabis extracts on CD45 leukocytes and several subpopulations in both murine and human immune cells as indicated by lower percentage of CXCR4+ cells and total CXCR4 cell surface expression (MFI). We identified two cannabinoids that when combined had the same effect as the whole extract. Notably, we tested different ratios of the two cannabinoids and the original ratio as in the plant was the most effective in reducing CXCR4 expression. These cannabinoids were also effective in attenuating DSS-induced acute colitis in-vivo. Administration of a whole-Cannabis extract or the two specific cannabinoids significantly ameliorated the severity of the disease as well as reduced CXCR4 in the inflamed colon. Collectively our results demonstrate that cannabinoids might attenuate inflammation through the modulation of CXCR4 axis.