Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States.
Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States.
Immunobiology. 2020 Jul;225(4):151956. doi: 10.1016/j.imbio.2020.151956. Epub 2020 May 30.
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.
对变应性真菌（Alternaria alternata）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（APCs）感知诱导细胞应激和代谢变化的环境干扰，对于过敏性气道炎症至关重要。然而，肺部 APC 对这种环境感应的机制尚不清楚。在这里，我们表明急性 Alternaria 挑战会迅速诱导气道中中性粒细胞的积累，并改变丙酮酸激酶（PKM2）和缺氧诱导因子-1α（Hif-1α）的表达，这与促炎介质的释放相关。体内阻断 IL33 信号会导致肺 APC 中的氧化应激和糖酵解减少。特异性敲除 CD11c 细胞可消除 Alternaria 诱导的中性粒细胞积累和炎症。此外，将 Alternaria 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 Alternaria 诱导的急性炎症中肺 APC 激活的关键调节剂。小分子 ML265 对 PKM2 的变构激活或 siRNA 介导的敲低与糖酵解和 APC 激活呈负相关。这些结果共同表明，真菌变应原 Alternaria 通过 PKM2 介导的糖酵解重编程影响肺 APC 的激活，从而促进急性气道炎症。我们的数据支持这样一种模型，即气道中的 Alternaria 致敏诱导了糖酵解和 PKM2 调节的电路，赋予了肺 APC 的急性激活，其靶向可能代表哮喘治疗的一种策略。
