A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses

Summary Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids. This evolutionarily conserved network architecture simultaneously reflected membrane lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in lipid abundance assigned distinct functional roles to individual lipid species organized across the network. This functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from lipid storage disorders, based solely on their altered membrane lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane lipid function in diverse biological systems.
Graphical Abstract
Highlights • Coregulation between membrane lipid species is organized in a circular network • The lipid network is conserved and reflects metabolism, localization, and adaptation • Sphingolipid metabolism regulates TLR trafficking, signaling, and cytokine release • Network-wide functional lipid annotations predict TLR responses in patient cells
Combining lipidomics with genetic perturbations in immune cells reveals the logic of inter-lipid regulatory structure and enables the functional assignment of lipids to different steps of Toll-like receptor signaling. Moreover, quantitative lipidomics alone can predict the inflammatory response of patient-derived cells.