Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms
DGKζ activates airways
Asthma is characterized by both T cell–mediated inflammation and airway smooth muscle cell hyperreactivity. In T cells, activation stimulates production of the second messenger diglycerol (DAG), which is converted into phosphatidic acid by diacylglycerol kinase ζ (DGKζ) to terminate DAG signaling. In a mouse model of asthma, Singh et al. found that genetic and pharmacological inhibition of DGK activity reduced both airway contraction and allergic inflammation. Unexpectedly, loss of DGKζ in immune and nonimmune cells had separable effects on allergic inflammation in the lung and airway hyperreactivity. Thus, DGK activity in both T cells and smooth muscle cells contributes to asthma, which is responsive to DGK inhibition in mice.
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.
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Supplementary Material
Summary
Fig. S1. DGKζ KO T cells display impaired TH2 differentiation in vitro.
Fig. S2. DGKζ KO T cells display attenuated TH2 differentiation at early time points.
Fig. S3. Addition of exogenous IL-4 restores TH2 differentiation in DGKζ KO T cells.
Fig. S4. DGKα KO mice are partially protected from OVA-induced allergic airway inflammation and AHR.
Fig. S5. Loss of DGKζ selectively impairs the ability of T cells to produce IL-4 in a T cell–intrinsic manner during TH2 differentiation in vivo.
Fig. S6. Myh11-Cre is not a driver of the reduction in tension of Myh11-Cre DGKfl/fl tracheal rings in response to methacholine.
Fig. S7. Inhibition of ERK signaling is sufficient to restore TH2 differentiation in DGKζ KO T cells.
Table S1. Flow cytometry antibodies.
Table S2. Immunoblotting antibodies.
Resources
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Science Signaling
Volume 12 | Issue 597
September 2019
September 2019
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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 14 March 2019
Accepted: 9 August 2019
Acknowledgments
We thank all members of the Kambayashi, Behrens, Koretzky, Su, Oliver, Silverman, Jordan, and Bassiri laboratories for the advice. We thank L. Samuelson (National Institutes of Health) and C. Sommers (National Institutes of Health) for providing us with the sevenmaker mice. We thank M. Li for carefully reviewing the statistical analyses performed in our studies. Funding: This work was supported by grants from the American Asthma Foundation (to T.K.), Tobacco-Related Disease Research Program (to A.H.), and the National Institutes of Health (F31-HL134325 to B.K.S.; T32HL007013 and T32ES007059 to C.H.F.; R21AI116121 and R01AI072197 to A.H.; and R01HL107589, R01HL111501, R01AI121250, and R01HL146645 to T.K.) Author contributions: B.K.S., W.L., A.M.S.P., A.H., R.A.P., D.A.D., and T.K. designed the experiments. B.K.S., W.L., A.M.S.P., M.Q.G., N.W., C.J.K.-W., and T.K. performed the experiments. C.H.F. and S.S.K. scored the histopathological specimens. M.J.R. and X.D. provided valuable reagents. T.K. conceived and supervised the project. The manuscript was written by B.K.S. and T.K. and edited by all authors. Competing interests: The authors declare that they have no competing financial interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.
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Funding Information
National Institutes of Health: F31-HL134325
National Institutes of Health: R21AI116121, R01AI072197
National Institutes of Health: R01HL107589, R01HL111501, R01AI121250, R01HL146645
American Asthma Foundation: Scholar Award
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