Mast Cell and TGF-β interactions in a model of Metabolic Dysfunction-Associated Steatotic Liver Disease and responses to cannabinoid intervention 2250623

Abstract Introduction Mast cells (MCs) are best known for their role in allergies, inflammation, and fibrosis, yet their contribution to metabolic associated steatotic liver disease (MASLD) remains unknown. MASLD is a progressive condition characterized by lipid accumulation, hepatocellular injury, and fibrosis. Only one approved therapy for MASLD exists with moderate effect. Methods To address this, we investigated MC and T cell populations in the livers of BALB/c mice with methionine and choline deficient diet (MCD) induced MASLD compared to healthy controls. Using ex vivo flow cytometry and cytokine multiplex assays, we quantified T cell response to the model. Using immunofluorescence microscopy, we identified and quantified MCs to assess whether their population size changes in MASLD. Results Our MASLD model successfully induced liver steatosis and liver injury with increases in pro-fibrotic and pro-inflammatory cytokines, validating its use for immunological studies. Ex vivo stimulation from control and MASLD livers demonstrated that cannabigerol (CBG) or CBG + cannabidiol (CBD), but not CBG alone, mitigated both helper and cytotoxic T cell activation (assessed by CD69, CD25, and IL-2 expression). TGF-β1 production was enhanced nearly 3-fold in the MASLD model, as expected, and this was restored to nearly control levels with CBG intervention. A similar pattern was observed with MC infiltration into the liver of MASLD mice with CBG intervention. Conclusion MC are a highly leverageable therapeutic target due to their unique expression of FceRI in solid tissue. These findings highlight MCs as potential targets of liver pathology and as an avenue for more affordable intervention via cannabinoids in a disease space that has relatively few effective alternatives. Funding Source NIDDK Grant 1R15DK131507-01A1 Topic Categories Immune Mechanisms of Human Disease (HUM)