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Sci Signal. 2019 Sep 3;12(597). pii: eaax3332. doi: 10.1126/scisignal.aax3332.

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

Author information

1
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Pulmonary, Critical Care and Sleep Division, University of California, Davis, Davis, CA 95616, USA.
3
Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ 08901, USA.
4
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
5
The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
6
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.
7
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. kambayat@pennmedicine.upenn.edu.

Abstract

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 (TH2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks TH2 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.

PMID:
31481522
DOI:
10.1126/scisignal.aax3332

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