Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms

作者：Brenal Singh, Wen Lu, Amanda M. Schmidt Paustian, Moyar Q. Ge, Cynthia Koziol‐White, Cameron H. Flayer, Sara S. Killingbeck, Nadan Wang, Xinzhong Dong, Matthew J. Riese, Deepak A. Deshpande, Reynold A. Panettieri, Angela Haczku, Taku Kambayashi · 发表于：Science Signaling · 年份：2019 · DOI：10.1126/scisignal.aax3332 · 被引用次数：31 · 研究领域：Asthma and respiratory diseases、Ion Channels and Receptors、Adipokines, Inflammation, and Metabolic Diseases

2 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.