DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases

Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGK alpha and DGK zeta as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGK alpha, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGK alpha activation is necessary for migration and a productive response. The role of DGK alpha in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGK alpha transcript. Together with in vitro experiments, this suggests that DGKs may represent potential therapeutic targets for disorders where inflammation, and neutrophils in particular, plays a major role. In this paper we focus on obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), but also rare genetic diseases such as alpha-1-antitrypsin deficiency. Indeed, the biological role of DGK alpha is understudied outside the T lymphocyte field. The recent wave of research aiming to develop novel and specific inhibitors as well as KO mice will allow a better understanding of DGK's role in neutrophilic inflammation. Better knowledge and pharmacologic tools may also allow DGK to move from the laboratory bench to clinical trials.