Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Pulmonary, Critical Care and Sleep Division, University of California, Davis, Davis, CA 95616, USA.
Sci Signal. 2019 Sep 3;12(597):eaax3332. doi: 10.1126/scisignal.aax3332.
Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (T2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks T2 differentiation. Here, we report that targeting diacylglycerol (DAG) kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protected against allergic asthma by simultaneously reducing airway inflammation and AHR though independent mechanisms. Targeted deletion of DGKζ in T cells decreased type 2 inflammation without reducing AHR. In contrast, loss of DGKζ in airway smooth muscle cells decreased AHR but not airway inflammation. T cell-specific enhancement of ERK signaling was only sufficient to limit type 2 airway inflammation, not AHR. Pharmacological inhibition of DGK diminished both airway inflammation and AHR in mice and also reduced bronchoconstriction of human airway samples in vitro. These data suggest that DGK is a previously unrecognized therapeutic target for asthma and reveal that the inflammatory and AHR components of asthma are not as interdependent as generally believed.
哮喘是一种由吸入性过敏原引起的慢性过敏性炎症性气道疾病，导致气道对收缩性刺激物的高反应性（AHR）和气道阻塞。阻断辅助性 T 细胞 2（T2）分化是治疗过敏性哮喘的一种可行的治疗策略，而强烈的 TCR 介导的 ERK 激活则阻止 T2 分化。在这里，我们报告靶向二酰基甘油（DAG）激酶 ζ（DGKζ），一种 DAG 介导的细胞信号转导的负调节剂，通过独立的机制同时减少气道炎症和 AHR，从而预防哮喘。在 T 细胞中靶向敲除 DGKζ 可减少 2 型炎症，而不降低 AHR。相比之下，气道平滑肌细胞中 DGKζ 的缺失减少了 AHR，但不减少气道炎症。T 细胞特异性增强 ERK 信号仅足以限制 2 型气道炎症，而不能限制 AHR。DGK 的药理学抑制在小鼠中既能减轻气道炎症又能减轻 AHR，还能减少体外人气道样本的支气管收缩。这些数据表明，DGK 是哮喘的一个以前未被认识的治疗靶点，并揭示了哮喘的炎症和 AHR 成分并不像普遍认为的那样相互依赖。
