Spontaneous Generation of an Endogenous RORγt Agonist

The transcription factor RORγt regulates the development of Th17 cells and their inflammatory cytokine IL-17─a pathway that can both clear bacterial pathogens and drive autoimmune diseases. An endogenous RORγt agonist with a noncanonical structure, a lysophosphatidylethanolamine (1-18:1-LPE or 1), was recently identified, and its identity both increases our understanding of immune regulation and creates options for therapeutic intervention. Compound 1 could be formed directly through enzymatic cleavage of a suitable phosphatidylethanolamine (PE) by a phospholipase A2 (PLA2) or by “triggering” of a suitable plasmalogen with accompanying 1,2-acyl migration from the sn-2 to sn-1 positions of glycerol. This study illustrates the plausibility of a plasmalogen-based pathway through synthesis of the plasmalogen precursor (2) and triggering the plasmalogen’s electron-rich vinyl ether with small electrophiles characteristic of inflammatory and tumor environments to create 1-18:1-LPE (1). The plasmalogen-based pathway is consistent with previous studies on the formation of 1, and it also conforms to Lands rules for acyl chain distribution and provides a mechanism for immune signaling with both spatial and temporal control.