The loss of DGK protects against allergic airway inflammation and airway hyperresponsiveness

Abstract

Abstract Asthma is a chronic allergic inflammatory airway disease that is caused by aberrant immune responses to inhaled allergens, which leads to airflow obstruction driven in part by increased sensitivity of airway smooth muscle to contractile agonists, a process known as airway hyperresponsiveness (AHR). The inflammation of allergic asthma is driven by type 2 cytokines released by Th2 CD4+ T cells and group 2 innate lymphoid cells (ILC2) in the lung. Here, we report that targeting DAG kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protects against allergic asthma. DGKζ knockout (KO) mice exhibited reduced type 2 airway inflammation and were completely resistant to AHR induction in a mouse model of allergic asthma. Surprisingly, the mechanism by which DGKζ protected against airway inflammation and AHR were separable. Targeted deletion of DGKζ in T cells led to decreased type 2 inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to decreased AHR despite no changes in airway inflammation. Importantly, the pharmacological inhibition of DGK provided protection against airway inflammation and AHR in mice, and also reduced bronchoconstriction of human airways. Together, our data suggest that DGKζ is potentially a novel therapeutic target for allergic asthma. Moreover, the targeted deletion of DGKζ reveals that the inflammatory and AHR components of allergic asthma are not as interdependent, as generally believed.