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

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 (DGK?), 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 DGK? in T cells decreased type 2 inflammation without reducing AHR. In contrast, loss of DGK? 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.

SUBMITTER: Singh BK

PROVIDER: S-EPMC6996596 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Singh Brenal K BK Lu Wen W Schmidt Paustian Amanda M AM Ge Moyar Q MQ Koziol-White Cynthia J CJ Flayer Cameron H CH Killingbeck Sara S SS Wang Nadan N Dong Xinzhong X Riese Matthew J MJ Deshpande Deepak A DA Panettieri Reynold A RA Haczku Angela A Kambayashi Taku T

Science signaling 20190903 597

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 (T<sub>H</sub>2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks T<sub>H</sub>2 differentiation. Here, we report that targeting diacylglycerol (DAG) kinase zeta (DGKζ), a negative regulator of D ...[more]

PMID: 31481522

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Project description:Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness. Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-GD 17.5 (IUGR group; term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control - normoxic and saline challenge; IUGR - hypoxic and saline challenge; Allergy - normoxic and OVA challenge; and IUGR + Allergy - hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry. Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue damping and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome. Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.

Dataset Information

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

Publications

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

Similar Datasets

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