IL-1/inhibitory kappa B kinase epsilon-induced glycolysis augment epithelial effector function and promote allergic airways disease

Xi Qian, Reem Aboushousha, Cheryl van de Wetering, Shi B. Chia, Eyal Amiel, Robert W. Schneider, Jos L. J. van der Velden, Karolyn G. Lahue, Daisy A. Hoagland, Dylan T. Casey, Nirav Daphtary, Jennifer L. Ather, Matthew J. Randall, Minara Aliyeva, Kendall E. Black, David G. Chapman, Lennart K. A. Lundblad, David H. McMillan, Anne E. Dixon, Vikas AnathyCharles G. Irvin, Matthew E. Poynter, Emiel F. M. Wouters, Pamela M. Vacek, Monique Henket, Florence Schleich, Renaud Louis, Albert van der Vliet, Yvonne M. W. Janssen-Heininger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Web of Science)

Abstract

Background: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. Objectives: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. Methods: We 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. Results: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1 beta into the 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-1 beta or IL-1 alpha resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1 beta- or IL-1 alpha-mediated proinflammatory responses and the stimulatory effects of IL-1 beta on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of kappa B kinase epsilon was downstream of HDM or IL-1 beta and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated 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 positive correlation was observed between sputum lactate and IL-1 beta levels, and lactate content correlated negatively with lung function. Conclusions: Collectively, these findings demonstrate that IL-1 beta/inhibitory kappa B kinase epsilon signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.
Original languageEnglish
Pages (from-to)435-450.e10
Number of pages26
JournalJournal of Allergy and Clinical Immunology
Volume142
Issue number2
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • Asthma
  • house dust mite
  • glycolysis
  • IL-1
  • inhibitor of kappa B kinase epsilon
  • lactate
  • lactate dehydrogenase A
  • DENDRITIC CELL ACTIVATION
  • HOUSE-DUST MITE
  • NLRP3 INFLAMMASOME
  • SEVERE ASTHMA
  • MURINE MODEL
  • LUNG-CANCER
  • INTERLEUKIN-1
  • HYPERRESPONSIVENESS
  • LACTATE
  • MICE
  • RESPONSES
  • METABOLISM
  • CELL ACTIVATION
  • INFLAMMATION
  • ASTHMA
  • ACTIVATION PROMOTES

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