Inhibiting Glycolysis and ATP Production Attenuates IL-33-Mediated Mast Cell Function and Peritonitis.

Cellular metabolism and energy sensing pathways are closely linked to inflammation, but there is little understanding of how these pathways affect mast cell function. Mast cells are major effectors of allergy and asthma, and can be activated by the alarmin IL-33, which is linked to allergic disease. Therefore, we investigated the metabolic requirements for IL-33-induced mast cell function, to identify targets for controlling inflammation. We found that IL-33 increases glycolysis, glycolytic protein expression, and oxidative phosphorylation (OX PHOS). Inhibiting OX PHOS had little effect on cytokine production, but antagonizing glycolysis with 2-deoxyglucose or oxamate suppressed inflammatory cytokine production and . ATP reversed this suppression. Glycolytic blockade suppressed IL-33 signaling, including ERK phosphorylation, NFκB transcription, and ROS production , and suppressed IL-33-induced neutrophil recruitment . To test a clinically relevant way to modulate these pathways, we examined the effects of the FDA-approved drug metformin on IL-33 activation. Metformin activates AMPK, which suppresses glycolysis in immune cells. We found that metformin suppressed cytokine production and , effects that were reversed by ATP, mimicking the actions of the glycolytic inhibitors we tested. These data suggest that glycolytic ATP production is important for IL-33-induced mast cell activation, and that targeting this pathway may be useful in allergic disease.