Cannabidiol perturbs macrophage polarization by interfering with the metabolic flux and PI3K/Akt pathway

Cannabinoids are increasingly used for medical application, yet the impact of specific cannabinoids on innate immune cells and the underlying molecular mechanisms remain controversial. In this study, we investigated the effect of cannabinoid, cannabidiol (CBD) on macrophage polarization toward M1 and M2 using murine bone marrow-derived macrophages (BMDM). CBD markedly inhibited IL-6 production and nitric oxide production without affecting TNF-α production in M1 polarized (LPS + IFN-γ-treated) macrophages. CBD treatment of M1 macrophages, however, increased expression of MHC II and CD86. On the other hand, CBD decreased key M2 markers, including CD206 and arginase-1, in IL-4-treated M2 macrophages. Mechanistically, CBD did not alter signaling downstream of TLR4 or IFN-γR (NF-κB, MAPK, and STAT1 pathways) but inhibited Akt phosphorylation in M1 macrophages. Metabolic flux analysis further revealed that CBD significantly enhanced glycolysis in M1 macrophages while reducing oxidative phosphorylation (OXPHOS) in M2 macrophages. Collectively, our findings revealed the multi-faceted effect of CBD on macrophage polarization by interfering with PI3K/Akt signaling and altering the metabolic flux. Taken together, our findings provide mechanistic insights into how CBD interferes with innate immune functions during macrophage polarization that may inform future therapeutic strategies utilizing cannabinoids.