Research ArticleAllergy

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

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Science Signaling  03 Sep 2019:
Vol. 12, Issue 597, eaax3332
DOI: 10.1126/scisignal.aax3332

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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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