Abstract 2031 Modulation of the cell membrane lipid milieu by peroxisomes triggers inflammatory responses

Phagocytosis, receptor-mediated signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes are crucial in fatty acid homeostasis and were recently found to regulate immune function. In Drosophila, we found that macrophages lacking peroxisomes had perturbed phospholipid profiles, which reduced host survival after infection. We used lipidomic, transcriptomic, and genetic screens to determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to activate macrophages. Loss of peroxisome function increased membrane phosphatidic acid (PA), and it unbalanced Diacylglycerol species (DAG) during infection, inhibiting Rho1, TNF pathway, and NFk-B-mediated responses. Peroxisome-glycerophospholipid-mediated signaling also controlled this immune signaling in mouse immune cells. While high levels of PA and DAG in cells without functional peroxisomes inhibited inflammatory phenotypes, many peroxisomes and low concentrations of cell membrane PA and DAG are features of immune cells from patients with the inflammatory disorders, Kawasaki Disease, Juvenile Idiopathic Arthritis, and Familial Mediterranean Fever. Our findings that peroxisomal lipid metabolism contributes to glycerophospholipid signaling to support immune cell function reveal new metabolic markers and potential therapeutic targets for immune diseases, metabolic disorders, and chronic inflammation. This work was funded by a Project Grant from the 2019-20 Establishment Grant (Research Nova Scotia), the CIHR Project grant PJT-169179 and NSERC Discovey Grant RGPIN-2019-04083 to Francesca Di Cara.