Nitration of GlcCer and Related Complex Lipids Enhances CD1d Binding Affinity and Modulates Immune Responses via Lipid Antigen Presentation to Natural Killer T Cells

Nitration of unsaturated lipids occurs through the action of the signaling molecule nitric oxide (NO) and related reactive nitrogen species. Derivatives of the most abundant glycolipid, β‐GlcCer, containing nitro‐unsaturated fatty acids are synthesized, and their biological functions are evaluated in comparison with corresponding phospholipids and α‐forms, as well as derivatives based on the endogenous α‐GalCer backbone. These NO 2 ‐modifed compounds exhibited higher binding affinity to CD1d, presumably due to the polar nitro group's “anchoring effect.” Despite their high CD1d binding affinity, nitrated β‐GlcCer demonstrates low cytokine‐inducing ability, similar to native β‐GlcCer, and exerted an inhibitory effect on CD1d‐mediated immune activation. These findings imply that nitrated lipids, which may increase during immune responses, could suppress CD1d‐triggered immune activity. This study sheds light on the potential roles of nitrated glycolipids and their effects on immune regulation.