Inositol-Requiring Enzyme 1 alpha-Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus-like Autoimmune Disease

Objective To explore the molecular mechanisms underlying dysregulation of lipid metabolism in the pathogenesis of systemic lupus erythematosus (SLE). Methods B cells in peripheral blood from patients with SLE and healthy controls were stained with BODIPY dye for detection of lipids. Mice with targeted knockout of genes for B cell-specific inositol-requiring enzyme 1 alpha (IRE-1 alpha) and stearoyl-coenzyme A desaturase 1 (SCD-1) were used for studying the influence of the IRE-1 alpha/SCD-1/SCD-2 pathway on B cell differentiation and autoantibody production. The preclinical efficacy of IRE-1 alpha suppression as a treatment for lupus was tested in MRL.Fas(lpr) mice. Results In cultures with mouse IRE-1 alpha-null B cells, supplementation with monounsaturated fatty acids largely rescued differentiation of plasma cells from B cells, indicating that the compromised capacity of B cell differentiation in the absence of IRE-1 alpha may be attributable to a defect in monounsaturated fatty acid synthesis. Moreover, activation with IRE-1 alpha/X-box binding protein 1 (XBP-1) was required to facilitate B cell expression of SCD-1 and SCD-2, which are 2 critical enzymes that catalyze monounsaturated fatty acid synthesis. Mice with targeted Scd1 gene deletion displayed a phenotype that was similar to that of IRE-1 alpha-deficient mice, with diminished B cell differentiation into plasma cells. Importantly, in B cells from patients with lupus, both IRE-1 alpha expression and Xbp1 messenger RNA splicing were significantly increased, and this was positively correlated with the expression of both Scd1 and Scd2 as well as with the amount of B cell lipid deposition. In MRL.Fas(lpr) mice, both genetic and pharmacologic suppression of IRE-1 alpha protected against the pathologic development and progression of lupus-like autoimmune disease. Conclusion The results of this study reveal a molecular link in the dysregulation of lipid metabolism in the pathogenesis of lupus, demonstrating that the IRE-1 alpha/XBP-1 pathway controls plasma cell differentiation through SCD-1/SCD-2-mediated monounsaturated fatty acid synthesis. These findings provide a rationale for targeting IRE-1 alpha and monounsaturated fatty acid synthesis in the treatment of patients with SLE.