DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases

Abstract

Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGKα and DGKζ as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGKα, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGKα activation is necessary for migration and a productive response. The role of DGKα in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGKα 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 DGKα 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.

Serum metabolomics analysis of patients with chronic obstructive pulmonary disease and ‘frequent exacerbator’ phenotype

“…Although thyroid hormones are suggested to serve a role in energy metabolism, inflammation and airway remodeling ( 78 , 79 ), their specific influence in the pathogenesis of COPD-FE remains uncertain, requiring additional research to clarify underlying mechanisms. DG, produced through phosphatidylinositol metabolism, is a lipid secondary messenger activated by extracellular stimuli ( 80 ). The innate and adaptive immune systems are crucial mechanisms for protecting against external pathogens.…”

Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling

“…Additionally, there are limited studies on the biological role of DGKα in the immune cells other than the T cells. However, increasing evidence indicates that DGKα regulates leukocyte function [209]. The stimulation of human neutrophils with N-formylmethionine-leucyl-phenylalanine promotes DAG production, most of which is metabolized by DGKα.…”

Role of Diacylglycerol Kinases in Acute Myeloid Leukemia

“…Class IV DGKs (i.e., DGKZ and DGKI) feature ankyrin repeats for protein-protein interaction. Finally, DGKQ, which belongs to Class V, harbors three C1 domains and a Ras association domain of unknown function [6].…”