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 <b>1</b>), was recently identified, and its identity both increases our understanding of immune regulation and creates options for therapeutic intervention. Compound <b>1</b> 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 <i>sn</i>-2 to <i>sn</i>-1 positions of glycerol. This study illustrates the plausibility of a plasmalogen-based pathway through synthesis of the plasmalogen precursor (<b>2</b>) and triggering the plasmalogen's electron-rich vinyl ether with small electrophiles characteristic of inflammatory and tumor environments to create 1-18:1-LPE (<b>1</b>). The plasmalogen-based pathway is consistent with previous studies on the formation of <b>1</b>, and it also conforms to Lands rules for acyl chain distribution and provides a mechanism for immune signaling with both spatial and temporal control.