Using a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, Chao and colleagues found that sphingolipid metabolism in astrocytes triggers the interaction between the C2 structural domain in cytoplasmic phospholipase A2 (cPLA2) and the CARD structural domain in mitochondrial antiviral signaling protein (MAVS), thereby facilitating an NF-κB-driven transcriptional program that promotes central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis [37]. This evidence concerns the gene MAVS and experimental autoimmune encephalomyelitis.