IL-1/inhibitory ?B kinase ?–induced glycolysis augment epithelial effector function and promote allergic airways disease - 09/12/17

Doi : 10.1016/j.jaci.2017.08.043

Xi Qian, PhD ^a, Reem Aboushousha, MS ^a,^{^{∗
These authors contributed equally to this work.}}, Cheryl van de Wetering, MS ^b,^{^{∗
These authors contributed equally to this work.}}, Shi B. Chia, MS ^a, Eyal Amiel, PhD ^c, Robert W. Schneider, BS ^a, Jos L.J. van der Velden, PhD ^a, Karolyn G. Lahue, BS ^a, Daisy A. Hoagland, BS ^a, Dylan T. Casey, BS ^a, Nirav Daphtary, MS ^d, Jennifer L. Ather, PhD ^d, Matthew J. Randall, PhD ^d, Minara Aliyeva, BS ^d, Kendall E. Black, BS ^d, David G. Chapman, PhD ^d,^g, Lennart K.A. Lundblad, PhD ^d, David H. McMillan, PhD ^a, Anne E. Dixon, MD ^d, Vikas Anathy, PhD ^a, Charles G. Irvin, PhD ^d, Matthew E. Poynter, PhD ^d, Emiel F.M. Wouters, MD, PhD ^b, Pamela M. Vacek, PhD ^e, Monique Henket, PhD ^f, Florence Schleich, MD ^f, Renaud Louis, MD, PhD ^f, Albert van der Vliet, PhD ^a, Yvonne M.W. Janssen-Heininger, PhD ^a,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, Vt
^d Department of Medicine, University of Vermont College of Medicine, Burlington, Vt
^e Medical Biostatistics Unit, University of Vermont College of Medicine, Burlington, Vt
^b Department of Pulmonology, Maastricht University Medical Center, Maastricht, The Netherlands
^c Department of Medical Laboratory and Radiation, University of Vermont College of Nursing and Health Sciences, Burlington, Vt
^f Department of Respiratory Medicine, CHU Sart-TilmanB35, Liege, Belgium
^g Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia

^∗Corresponding author: Yvonne M. W. Janssen-Heininger, PhD, Department of Pathology and Laboratory Medicine, University of Vermont, HSRF Building, Room 216A, Burlington, VT 05405.Department of Pathology and Laboratory MedicineUniversity of VermontHSRF Building, Room 216ABurlingtonVT05405

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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-1β 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-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β– or IL-1α–mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)–induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β 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-1β levels, and lactate content correlated negatively with lung function.

Conclusions

Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

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Graphical abstract

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Key words : Asthma, house dust mite, glycolysis, IL-1, inhibitor of κB kinase ε, lactate, lactate dehydrogenase A

Abbreviations used : AHR, BAL, BMI, DC, 2-DG, ECAR, HDM, HK2, IKK, IL-1RI, KC, LDHA, MTE, mTOR, NEC, Rn, siRNA, TBK1, TSLP, WT

Plan

Methods

Subjects' characteristics

Increases in glycolysis in lungs from mice with HDM-induced allergic airways disease

An adaptive immune response and IL-1 signaling are required for increases in glycolysis in lungs of mice with HDM-induced allergic airways disease

Increased glycolysis promotes IL-1α– and IL-1β–mediated proinflammatory responses in airway epithelial cells and augments release of proinflammatory mediators after subsequent exposure to HDM

IKKε promotes IL-1β–induced glycolysis in epithelial cells and HDM-induced allergic airways disease in mice

LDHA augments lactate levels in lung tissue and contributes to HDM-induced allergic airways disease

Evidence for increased glycolysis in asthmatic patients in association with airway neutrophil counts

Discussion

Supported National Institutes of Health (NIH) grants R01 HL060014 and HL079331; R35 HL135828 (to Y.M.W.J.-H.), R01 HL122383 (to V.A.), R01 HL085646, and ES021476 (to A.v.d.V.); HL130847 (to A.E.D.); R01 HL133920 (M.E.P. and A.E.D.); and NIH/National Institute of Allergy and Infectious Diseases 1R21AI112804 and NIH/National Center for Research Resources P30 GM103532 (to L.K.A.L.), as well as VLC CoBRE: P30GM103532 and VCIID CoBRE: P20GM103496 (M.E.P.), UVM College of Nursing and Health Sciences Start-up Funds (to E.A.), and research grants from GlaxoSmithKline (to R.L.), Novartis (to R.L.), and Chiesi (to R.L. and E.F.M.W.).

Disclosure of potential conflict of interest: R. Aboushousha, C. van de Wetering, D. A. Hoagland, and D. T. Casey have received grants from the National Institutes of Health (NIH; R01 HL060014) L. K. A. Lundblad has received a grant from the NIH/National Institute of Allergy and Infectious Disease and has stock/stock options in Pfizer. A. E. Dixon has consultant arrangements with Roche, has received grants from NIH and Pfizer, and has received travel support from Boehringer Ingelheim. V. Anathy has received grants from the National Heart, Lung, and Blood Institute (R0122383, HL135828). C. G. Irvin has received a grant from the NIH and has relationships with Acorda, MGC, and Methapharm. M. E. Poynter has received grants from the NIH; has received payments for lectures from Louisiana State University School of Veterinary Medicine, the University of Utah School of Medicine, and Genentech; and has received travel support from Louisiana State University School of Veterinary Medicine, the University of Utah School of Medicine, and Genentech. E. F. M. Wouters has board memberships with Nycomed and Boehringer, has received grants from AstraZeneca and GlaxoSmithKline, and has received payment for lectures from AstraZeneca, GlaxoSmithKline, Novartis, and Chiesi. P. M. Vacek has received a grant from the NIH. R. Louis has board memberships with GlaxoSmithKline, AstraZeneca, and Novartis and has received grants from GlaxoSmithKline, AstraZeneca, and Novartis. A. van der Vliet has received grants from the National Heart, Lung, and Blood Institute (HL084646) and the National Institute of Environmental Health Sciences. Y. M. W. Janssen-Heininger has received grants from the NIH (R01HL060014). The rest of the authors declare that they have no relevant conflicts of interest.