The Molecular Logic of Platelet-Activating Factor (PAF)

Abstract Platelet-activating factor (PAF) is a well-known if enigmatic lipid signal with important roles in inflammatory responses, allergic reactions, autoimmune diseases, and thrombotic cascades. Several lines of evidence suggest that our current model of PAF’s molecular mechanism is inadequate. This report describes a recontextualized model for PAF. The revised model embeds PAF in a plasmalogen-based molecular mechanism in which activation is a spontaneous chemical reaction triggered by environmental conditions that liberates a PAF receptor (PAF-R) agonist from a membrane-bound phospholipid. The active ligand subsequently undergoes a thermodynamically driven spontaneous rearrangement into an inactive isomer, a feature that controls response lifetime. The revised model is a molecule-autonomous set of transformations that create a response with spatial and temporal control. More generally the revised model’s congruence with a similar model for RORγt supports a picture in which plasmalogens form a part of the immune system that is separate from the cell-based innate and adaptive immune systems.