| Abstract: | Background: Recent preclinical and clinical studies have suggested a potential anti‐inflammatory effect of metformin, an anti‐diabetic drug, beyond its glucose‐lowering activity. We have recently found that the aryl hydrocarbon receptor (AhR, a cellular chemical sensor)‐ligand axis is critical in modulating mast cell response via, in part, the induction of ER/mitochondrial stress response. However, the potential regulatory effect of metformin on mast cell function and allergic responses remains unknown. We aimed to test a hypothesis that metformin may play a role in modulating AhR‐mediated activation of mast cells with or without the combined stimulation with cross‐linkage of antigen and IgE. Method: Varying doses (1 μM‐1 mM) of metformin was evaluated for its effect on AhR‐mediated mast cell degranulation as measured by the level of hexosaminidase release, cytokine levels (TNF‐a and IL‐13) by ELISA and intracellular calcium by measuring the ratio of Fluo‐4 vs Fura red fluorescent dyes in murine bone marrow‐derived mast cells (BMMCs) with or without the stimulation in vitro by cross‐linkage with ovalbumin (OVA) and anti‐OVA IgE Abs and in vivo by assessing the level of passive cutaneous anaphylaxis (PCA). Results: Metformin at relatively low doses (1‐10 μM) was shown to mildly suppress IgE‐mediated responses, including degranulation (34% reduction, P = 0.0135), TNF‐α (23% reduction, P = 0.0139) and IL‐13 (38% reduction, P = 0.0015) secretions in BMMCs. Importantly, metformin at the same doses potently inhibited mast cell responses in all parameters (100% reduction, P < 0.0001 for degranulation; 87% reduction, P < 0.0001 for TNF‐α; 90% reduction, P < 0.0001 for IL‐13) in mast cells treated with an AhR ligand, 5,11‐dihydroindolo[ 3,2‐b]carbazole‐6‐carbaldehyde (FICZ). Mechanistically, its inhibitory effect was mediated through the suppression of FICZ‐induced MAPK activation, intracellular calcium release and ROS generation. Metformin also blocked AhR‐mediated PCA in vivo (90% reduction, P < 0.0001). Conclusion: Metformin, a common anti‐diabetic agent, was shown to exert inhibitory effect on AhR‐mediated mast cell activation in vitro and in vivo, suggesting its potential utility as a newer form of therapy for asthma and allergic diseases; this is particularly relevant when considering the adverse effect of the exposure to environmental polycyclic aromatic hydrocarbons. |
