IL-1/inhibitory κB kinase ε–induced glycolysis augment epithelial effector function and promote allergic airways disease

摘要

BackgroundEmerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma.ObjectivesWe sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma.MethodsWe examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis.ResultsIn a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1dependent manner. Furthermore, administration of IL-1?into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A爋ccurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1?or IL-1?resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1? or IL-1?mediated proinflammatory responses and the stimulatory effects of IL-1?on house dust mite (HDM)induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of 築 kinase ?was downstream of HDM or IL-1?and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A燼ttenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A爌ositive correlation was observed between sputum lactate and IL-1?levels, and lactate content correlated negatively with lung function.ConclusionsCollectively, these findings demonstrate that IL-1?inhibitory 築 kinase ?signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.