Nitration of GlcCer and related complex lipids enhances CD1d bind-ing affinity and modulates immune responses via lipid antigen presentation to NKT cells

Nitration of unsaturated lipids occurs through the action of the signaling molecule nitric oxide (NO) and re-lated reactive nitrogen species (RNS). Derivatives of the most abundant glycolipid, α-GlcCer, containing nitro-unsaturated fatty acids were synthesized, and their biological functions were evaluated in comparison with corresponding phospholipids and -forms, as well as derivatives based on the endogenous α-GalCer backbone. These NO2-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 α-GlcCer demonstrated low cyto-kine-inducing ability, similar to native -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.