TY - JOUR
T1 - Pyruvate Kinase M2 Promotes Expression of Proinflammatory Mediators in House Dust Mite-Induced Allergic Airways Disease
AU - van de Wetering, Cheryl
AU - Aboushousha, Reem
AU - Manuel, Allison M.
AU - Chia, Shi B.
AU - Erickson, Cuixia
AU - MacPherson, Maximilian B.
AU - van der Velden, Jos L.
AU - Anathy, Vikas
AU - Dixon, Anne E.
AU - Irvin, Charles G.
AU - Poynter, Matthew E.
AU - van der Vliet, Albert
AU - Wouters, Emiel F. M.
AU - Reynaert, Niki L.
AU - Janssen-Heininger, Yvonne M. W.
N1 - Funding Information:
This work was supported by National Institutes of Health R01 HL137268 and an unrestricted grant from Chiesi.
Publisher Copyright:
Copyright Ó 2020 by The American Association of Immunologists, Inc.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1-induced glycolytic reprogramming contributes to allergic airway disease using a murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well as in nasal epithelial cells from asthmatics as compared with healthy controls. Although the tetramer form of PKM2 converts phosphoenolpyruvate to pyruvate, the dimeric form of PKM2 has alternative, nonglycolysis functions as a transcriptional coactivator to enhance the transcription of several proinflammatory cytokines. In the current study, we examined the impact of PKM2 on the pathogenesis of house dust mite-induced allergic airways disease in C57BL/6NJ mice. We report, in this study, that activation of PKM2, using the small molecule activator, TEPP46, augmented PKM activity in lung tissues and attenuated airway eosinophils, mucus metaplasia, and subepithelial collagen. TEPP46 attenuated IL-1 beta-mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1 beta-mediated increases in thymic stromal lymphopoietin (TSLP) and GM-CSF in primary tracheal epithelial cells isolated from C57BL/6NJ mice. We also demonstrate that IL-1 beta-mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1 beta-induced release of TSLP and GM-CSF, suggesting that the ability of PKM2 to phosphorylate STAT3 contributes to its proinflammatory function. Collectively, these results demonstrate that the glycolysis-inactive form of PKM2 plays a crucial role in the pathogenesis of allergic airways disease by increasing IL-1 beta-induced proinflammatory signaling, in part, through phosphorylation of STAT3.
AB - Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1-induced glycolytic reprogramming contributes to allergic airway disease using a murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well as in nasal epithelial cells from asthmatics as compared with healthy controls. Although the tetramer form of PKM2 converts phosphoenolpyruvate to pyruvate, the dimeric form of PKM2 has alternative, nonglycolysis functions as a transcriptional coactivator to enhance the transcription of several proinflammatory cytokines. In the current study, we examined the impact of PKM2 on the pathogenesis of house dust mite-induced allergic airways disease in C57BL/6NJ mice. We report, in this study, that activation of PKM2, using the small molecule activator, TEPP46, augmented PKM activity in lung tissues and attenuated airway eosinophils, mucus metaplasia, and subepithelial collagen. TEPP46 attenuated IL-1 beta-mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1 beta-mediated increases in thymic stromal lymphopoietin (TSLP) and GM-CSF in primary tracheal epithelial cells isolated from C57BL/6NJ mice. We also demonstrate that IL-1 beta-mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1 beta-induced release of TSLP and GM-CSF, suggesting that the ability of PKM2 to phosphorylate STAT3 contributes to its proinflammatory function. Collectively, these results demonstrate that the glycolysis-inactive form of PKM2 plays a crucial role in the pathogenesis of allergic airways disease by increasing IL-1 beta-induced proinflammatory signaling, in part, through phosphorylation of STAT3.
KW - THYMIC STROMAL LYMPHOPOIETIN
KW - GROWTH-FACTOR RECEPTOR
KW - EPITHELIAL-CELLS
KW - NUCLEAR TRANSLOCATION
KW - PKM2
KW - INFLAMMATION
KW - INHIBITION
KW - ISOFORM
KW - GENE
KW - TRANSCRIPTION
U2 - 10.4049/jimmunol.1901086
DO - 10.4049/jimmunol.1901086
M3 - Article
C2 - 31924651
SN - 0022-1767
VL - 204
SP - 763
EP - 774
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -