Key Points A small molecular activator of PKM2 attenuates allergic airways disease in mice. Activation of PKM2 decreases IL-1β–induced airway inflammation. PKM2 activation decreases IL-1β–induced nuclear phosphorylation of STAT3. 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-1β–mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1β–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-1β–mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1β–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-1β–induced proinflammatory signaling, in part, through phosphorylation of STAT3.

中文翻译：

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丙酮酸激酶 M2 促进室内尘螨引起的过敏性气道疾病中促炎介质的表达

关键点 PKM2 的一种小分子激活剂可减轻小鼠的过敏性气道疾病。PKM2 的激活减少了 IL-1β 诱导的气道炎症。PKM2 激活降低 IL-1β 诱导的 STAT3 核磷酸化。哮喘是一种慢性疾病，其特征是炎症、粘液化生、气道重塑和高反应性。我们最近使用鼠屋尘螨模型表明，IL-1 诱导的糖酵解重编程会导致过敏性气道疾病。此外，与健康对照相比，该模型以及哮喘患者的鼻上皮细胞中丙酮酸激酶 M2 (PKM2) 的水平增加。尽管 PKM2 的四聚体形式将磷酸烯醇式丙酮酸转化为丙酮酸，但 PKM2 的二聚体形式具有替代性，非糖酵解作用作为转录共激活因子来增强几种促炎细胞因子的转录。在目前的研究中，我们检查了 PKM2 对 C57BL/6NJ 小鼠房尘螨诱发的过敏性气道疾病发病机制的影响。在本研究中，我们报告了使用小分子激活剂 TEPP46 激活 PKM2，增强了肺组织中的 PKM 活性，并减弱了气道嗜酸性粒细胞、粘液化生和上皮下胶原蛋白。TEPP46 减弱了 IL-1β 介导的气道炎症和促炎介质的表达。暴露于 TEPP46 强烈降低了从 C57BL/6NJ 小鼠分离的原代气管上皮细胞中 IL-1β 介导的胸腺基质淋巴细胞生成素 (TSLP) 和 GM-CSF 的增加。我们还证明 IL-1β 介导的核磷酸化 STAT3 增加被 TEPP46 降低。最后，STAT3 抑制减弱了 IL-1β 诱导的 TSLP 和 GM-CSF 的释放，表明 PKM2 磷酸化 STAT3 的能力有助于其促炎功能。总的来说，这些结果表明 PKM2 的糖酵解非活性形式通过增加 IL-1β 诱导的促炎信号传导，部分通过 STAT3 的磷酸化，在过敏性气道疾病的发病机制中起着至关重要的作用。