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

Xi Qian, PhDa, Reem Aboushousha, MS#a, Cheryl van de Wetering, MS#b, Shi B. Chia, MSa, Eyal Amiel, PhDc , Robert W. Schneider, BSa, Jos LJ van der Velden, PhDa, Karolyn G. Lahue, BSa, Daisy A. Hoagland, BSa, Dylan T. Casey, BSa, Nirav Daphtary, MSd, Jennifer L. Ather, PhDd, Matthew J. Randall, PhDd, Minara Aliyeva, BSd, Kendall E. Black, BSd, David G. Chapman, PhDd,g, Lennart K. A. Lundblad, PhDd, David H. McMillan, PhDa, Anne E. Dixon, MDd, Vikas Anathy, PhDa, Charles G. Irvin, PhDd, Matthew E. Poynter, PhDd, Emiel. F.M. Wouters, MD, PhDb, Pamela M. Vaceke, Monique Henket, PhDf , Florence Schleich, MDf , Renaud Louis, MD, PhDf , Albert van der Vliet, PhDa, and Yvonne M. W. Janssen-Heininger, PhDa,*

J Allergy Clin Immunol 29/08/2018

PMID: 29108965


Background: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in allergic asthma. Objectives: Here we sought to determine if glycolysis is altered in allergic asthma and to address its importance in the pathogenesis of allergic asthma. Methods: We examined alterations in glycolysis in sputum samples from asthmatics 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.

Results: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1- dependent manner. Furthermore, administration of IL-1β into airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose usage, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated pro-inflammatory responses and the stimulatory effects of IL-1β on HDMinduced release of TSLP, and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of house dust mite (HDM) or IL-1β, and was required for HDM-induced glycolysis and the pathogenesis of allergic airways disease. SiRNA-ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatics intrinsically produced more lactate as compared to cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatics, notably those patients with >61% neutrophils. A positively correlation was observed between sputum lactate and IL-1β, and lactate content negatively correlated with lung function. Conclusions: Collectively, these findings demonstrate that IL-1β/IKKε signaling plays an important role in HDM-induced glycolysis and the pathogenesis of allergic airways disease.