The role and regulation of phospholipase D in infectious and inflammatory diseases

Phospholipase D (PLD) hydrolyzes phosphatidylcholine into phosphatidic acid (PA) and free choline. Two mammalian PLD isoforms, PLD1 and PLD2, play essential roles in the regulation of infectious and inflammatory human diseases. Many innate immune cells including neutrophils and macrophages express both PLD isoforms, and activation of PLD elicits leukocyte migration, phagocytosis, and generation of reactive oxygen species to increase innate defense activity. However, PLD2 activation blocks neutrophil extracellular trap formation, suggesting nuanced roles for PLD in cellular activities. Indeed, in addition to their normal physiologic roles, PLD1 and/or PLD2 also contribute to the pathomechanism of various human inflammatory diseases. Many studies have demonstrated that PLD exacerbates pathogenic inflammatory responses present in various respiratory, cardiovascular, retinal, intestinal, metabolic, and autoimmune diseases. Thus, PLD isoforms are attractive, druggable enzymatic mediators that hold great promise as targets for therapeutic intervention in many human infectious and inflammatory diseases.