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

Brenal K. Singh, Wen Lu, Amanda M. Schmidt Paustian, Moyar Q. Ge, Cynthia J. Koziol-White, Cameron H. Flayer, Sara S. Killingbeck, Nadan Wang, Xinzhong Dong, Matthew J. Riese, Deepak A. Deshpande, Reynold A. Panettieri, Angela Franciska Haczku, Taku Kambayashi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numberaax3332
JournalScience Signaling
Volume12
Issue number597
DOIs
StatePublished - Sep 3 2019

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Diacylglycerol Kinase
Asthma
Inflammation
T-Lymphocytes
Bronchoconstriction
Diglycerides
Airway Obstruction
Allergens
Smooth Muscle Myocytes
T-cells
Pharmacology
Therapeutics
Cell signaling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Singh, B. K., Lu, W., Schmidt Paustian, A. M., Ge, M. Q., Koziol-White, C. J., Flayer, C. H., ... Kambayashi, T. (2019). Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms. Science Signaling, 12(597), [aax3332]. https://doi.org/10.1126/scisignal.aax3332

Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms. / Singh, Brenal K.; Lu, Wen; Schmidt Paustian, Amanda M.; Ge, Moyar Q.; Koziol-White, Cynthia J.; Flayer, Cameron H.; Killingbeck, Sara S.; Wang, Nadan; Dong, Xinzhong; Riese, Matthew J.; Deshpande, Deepak A.; Panettieri, Reynold A.; Haczku, Angela Franciska; Kambayashi, Taku.

In: Science Signaling, Vol. 12, No. 597, aax3332, 03.09.2019.

Research output: Contribution to journalArticle

Singh, BK, Lu, W, Schmidt Paustian, AM, Ge, MQ, Koziol-White, CJ, Flayer, CH, Killingbeck, SS, Wang, N, Dong, X, Riese, MJ, Deshpande, DA, Panettieri, RA, Haczku, AF & Kambayashi, T 2019, 'Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms', Science Signaling, vol. 12, no. 597, aax3332. https://doi.org/10.1126/scisignal.aax3332
Singh, Brenal K. ; Lu, Wen ; Schmidt Paustian, Amanda M. ; Ge, Moyar Q. ; Koziol-White, Cynthia J. ; Flayer, Cameron H. ; Killingbeck, Sara S. ; Wang, Nadan ; Dong, Xinzhong ; Riese, Matthew J. ; Deshpande, Deepak A. ; Panettieri, Reynold A. ; Haczku, Angela Franciska ; Kambayashi, Taku. / Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms. In: Science Signaling. 2019 ; Vol. 12, No. 597.
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