Dual Modulation of Macrophage and Dendritic Cell Responses to BCG by CB2 Receptor Agonists

Tuberculosis (TB) remains a global health challenge due to its capacity for immune evasion, latent persistence, and increasing antibiotic resistance. Host-directed therapies targeting the immune system have gained attention as promising alternatives. Here, we investigate the immunomodulatory effects of cannabinoid receptor type 2 (CB2) agonists on two key innate immune cells—macrophages and dendritic cells (DCs)—in the context of Mycobacterium bovis BCG infection. In J774A.1 macrophages, pretreatment with GP1a, JWH-133, and GW833972A significantly reduced iBCG-induced production of TNF-α, IL-6, PGE2, and nitric oxide. GP1a also downregulated pro-inflammatory and lipid metabolism genes, suppressed lipid droplet formation, and inhibited NF-κB activation. In murine bone marrow-derived DCs, post-infection treatment with GP1a decreased BCG-induced TNF-α and IL-1β without impairing expression of MHC-I, MHC-II, or CD80, suggesting preserved antigen-presenting capacity. Additionally, GP1a appeared to reduce the intracellular bacterial burden in DCs. These findings provide novel evidence that CB2 agonists modulate both inflammatory and metabolic pathways in innate immune responses to mycobacteria. By demonstrating convergent effects across distinct cell types and infection models (iBCG and live BCG-GFP), our data support CB2 targeting as a viable strategy for host-directed immunotherapy in TB.