Inositol‐Requiring Enzyme 1α–Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus‐like Autoimmune Disease
Yana Zhang, Ming Gui, Yajun Wang, Nikita Mani, Shuvam Chaudhuri, Beixue Gao, Huabin Li, Yashpal S. Kanwar, Sarah Lewis, Sabrina N. Dumas, James M. Ntambi, Kezhong Zhang, Deyu Fang
Abstract
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 1α (IRE‐1α) and stearoyl‐coenzyme A desaturase 1 (SCD‐1) were used for studying the influence of the IRE‐1α/SCD‐1/SCD‐2 pathway on B cell differentiation and autoantibody production. The preclinical efficacy of IRE‐1α suppression as a treatment for lupus was tested in MRL.Fas lpr mice. Results In cultures with mouse IRE‐1α–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‐1α may be attributable to a defect in monounsaturated fatty acid synthesis. Moreover, activation with IRE‐1α/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‐1α – deficient mice, with diminished B cell differentiation into plasma cells. Importantly, in B cells from patients with lupus, both IRE‐1α 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‐1α 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‐1α/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‐1α and monounsaturated fatty acid synthesis in the treatment of patients with SLE.