Sensitivity to allergenic fungi (Alternaria alternata) is associated with acute, severe asthma attacks. Antigen presenting cells (APCs) in the lung sense environmental perturbations that induce cellular stress and metabolic changes and are critical for allergic airway inflammation. However, the mechanisms underlying such environmental sensing by APCs in the lung remains unclear. Here we show that acute Alternaria challenge rapidly induces neutrophil accumulation in airways, and alter expressions of Pyruvate Kinase (PKM2) and hypoxia-inducible factor -1α (Hif-1α) that correlates with proinflammatory mediator release. Blockade of IL33 signaling in vivo led to reduce oxidative stress and glycolysis in lung APCs. Lung-specific ablation of CD11c⁺ cells abrogates Alternaria-induced neutrophil accumulation and inflammation. Furthermore, administration of Alternaria into the airways stimulated APCs and elevate the expression of Glut-1. Mechanistically, we establish that PKM2 is a critical modulator of lung APC activation in Alternaria-induced acute inflammation. Allosteric activation of PKM2 by a small molecule ML265 or siRNA-mediated knock down correlated negatively with glycolysis and activation of APCs. These results collectively demonstrates that PKM2-mediated glycolytic reprogramming by fungal allergen Alternaria influences lung APC activation, thereby promotes acute airway inflammation. Our data support a model in which Alternaria sensitization in airways induce a circuitry of glycolysis and PKM2 regulation that confers an acute activation of APCs in the lung, whose targeting might represent a strategy for asthma treatment.

对过敏性真菌（链格孢）的敏感性与急性、严重的哮喘发作有关。肺部的抗原呈递细胞 (APC) 能够感知环境扰动，从而诱发细胞应激和代谢变化，对过敏性气道炎症至关重要。然而，肺部 APC 进行环境感知的机制仍不清楚。在这里，我们发现急性链格孢菌攻击会迅速诱导气道中性粒细胞积聚，并改变与促炎介质释放相关的丙酮酸激酶（PKM2）和缺氧诱导因子-1α（Hif-1α）的表达。体内IL33 信号传导的阻断可减少肺 APC 中的氧化应激和糖酵解。^{CD11c +}细胞的肺部特异性消融消除了链格孢属诱导的中性粒细胞积累和炎症。此外，将链格孢菌注入气道会刺激 APC 并提高 Glut-1 的表达。从机制上讲，我们确定 PKM2 是链格孢属引起的急性炎症中肺 APC 激活的关键调节剂。小分子 ML265 或 siRNA 介导的敲低对 PKM2 的变构激活与糖酵解和 APC 的激活呈负相关。这些结果共同表明，真菌过敏原链格孢属(Alternaria)介导的 PKM2 介导的糖酵解重编程影响肺 APC 激活，从而促进急性气道炎症。我们的数据支持一个模型，其中气道中的链格孢致敏诱导了糖酵解和 PKM2 调节回路，从而导致肺部 APC 的急性激活，其靶向可能代表了哮喘治疗的策略。