A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility

Abstract The cellular lipidome is comprised of thousands of unique lipid species. Herein, using mass spectrometry-based targeted lipidomics we have characterized the lipid landscape of human and mouse immune cells (www.cellularlipidatlas.com). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide new insights into immune cell biology, we determined how a cell-specific lipid trait, differences in the abundance of poly-unsaturated fatty acid-containing glycerophospholipids (PUFA-PLs), influenced immune cell biology. We firstly show that differences in PUFA-PL content underpins the differential susceptibility of immune cells to ferroptosis, and secondly, that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and cell-specific lipid phenotypes underpin aspects of immune cell physiology.