Biosynthesis of esterified oxidized fatty acids in leukocytes and their biological role

• Applicants: Professor Dr. Nils Helge Schebb; Professor Dr. Dieter Steinhilber
• Subject Area: Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557734767

The resolution of inflammation was believed to be mediated by specific multiple-hydroxylated PUFA generated by the consecutive action of 5-LO and 15-LO, but formation, occurrence and signaling of these molecules could not be confirmed. However, large amounts of mono-hydroxy-PUFA and significant amounts of dihydroxy-PUFA are detected. The major portion of these LO products are found esterified in phospholipids in membranes with yet unknown biological role. In the project we follow the hypothesis that the esterified LO derived oxylipins are important mediators in the regulation of resolution of inflammation. We investigate in detail the formation of esterified hydroxy-PUFA in human primary leukocytes. New liquid chromatography high-resolution mass spectrometry methods are developed and applied to characterize the oxylipin bearing phospholipids together with state of the art targeted oxylipin metabolomics approaches. The mechanism of formation of esterified hydroxy-PUFA is then elucidated using stably transfected cells with the enzymes of the Lands cycle and different LO as well as the use of specific isotopically labeled oxylipins as probes. Finally, the role of esterified oxylipins in macrophage biology (differentiation, cytokine release, NFkappaB signaling, oxidative burst) is characterized and the esterified lipid oxylipins are analyzed in samples from patients. Overall, this project will lead to a better understanding of the relevance of lipid mediators in the regulation of inflammation.

• DFG Programme: Research Grants