Uridine metabolism drives SLE-like autoimmunity by regulating B cell metabolic networks 3165

Abstract Description Although various metabolic pathways are implicated in autoimmune B and T cell responses in SLE, the role of nucleotide metabolism in SLE autoimmunity is unknown. Here we show that de novo uridine synthesis is critical in development of SLE autoimmunity. SLE-prone FcγRIIB-/- mice treated with an inhibitor of de novo uridine synthesis exhibit reduced germinal center (GC) B cell and plasma cell (PC) responses, reduced serum autoantibody titers, and reduced splenic autoantibody forming cells. B cells from treated FcγRIIB-/- mice demonstrate reduced oxidative phosphorylation (OXPHOS) and ATP production. Decreased expression of fatty acid oxidation (FAO) enzyme CPT1A and reduced levels of palmitoylcarnitine, a FAO intermediate, in B cells from treated FcγRIIB-/- mice indicate that de novo uridine synthesis promotes FAO as a source of ATP in FcγRIIB-/- B cells. B cells from treated mice further demonstrate build-up of glucose-6-phosphate and pyruvate, suggesting that de novo uridine synthesis drives glucose flux through the TCA cycle and OXPHOS. Increased glutamine and glutamate in B cells from treated FcγRIIB-/- mice suggest a compensatory flux through glutaminolysis to supplement loss of ATP production. Our data suggest that uridine metabolism promotes SLE-associated GC and PC responses by regulating B cell metabolic networks, in addition to its role in synthesis of nucleic acid and protein, to meet the energy demands of GC B cells and PCs. Funding Sources Supported by: 1R01AI162971-04 Judy S. Finkelstein Memorial Student Research Award Topic Categories Basic Autoimmunity (BA)