Diacylglycerol kinase zeta deficiency attenuates papain-induced type 2 airway inflammation

Allergic airway diseases are caused by inappropriate immune responses directed against inhaled environmental antigens. We previously reported that the inhibition of diacylglycerol (DAG) kinase ζ (DGKζ), an enzyme that terminates DAG-mediated signaling, protects against T cell-mediated allergic airway inflammation by blocking Th2 cell differentiation. In this study, we tested whether DGKζ deficiency also affects allergic airway disease mediated by type 2 innate lymphoid cells (ILC2)s. DGKζ-deficient mice displayed diminished ILC2 function and reduced papain-induced airway inflammation compared to wildtype mice. Unexpectedly, however, mice with hematopoietic cell-specific deletion of DGKζ displayed intact airway inflammation upon papain challenge. Rather, bone marrow chimera studies revealed that DGKζ deficiency in the non-hematopoietic compartment was responsible for the reduction in papain-induced airway inflammation. These data suggest that DGK might represent a novel therapeutic target not only for T cell-dependent but also ILC2-dependent allergic airway inflammation by affecting non-hematopoietic cells.