IRE1α-mediated monounsaturated fatty acid synthesis drives B cell differentiation and lupus-like autoimmune disease

Arthritis Rheumatol. 2021 Jun 8. doi: 10.1002/art.41883. Online ahead of print.

Abstract

Objectives: This study is to explore the molecular mechanisms underlying how the lipid metabolic dysregulation is associated with systemic lupus erythematosus (SLE) pathogenesis.

Methods: B cells in peripheral blood from lupus patients and healthy controls were used for lipid bodipy analysis. B-cell specific IRE1α and SCD1 knockout mice were employed for studying the influence of IRE1α-SCD1/2 pathway on B-cell differentiation and auto-antibody production. The preclinical efficacy of IRE1α suppression in lupus treatment were elucidated in MRL/Lpr mice.

Results: We showed that supplementation of the monounsaturated fatty acid largely rescues plasma cell differentiation from IRE1α-null B cells, indicating that the frailer of IRE1α-null B-cell differentiation is due to a defect in monounsaturated fatty acid synthesis. IRE1α-XBP-1 activation is required for B cell expression of stearoyl-CoA desaturase 1 and 2 (SCD1 and SCD2), two critical enzymes catalyzing monounsaturated fatty acid synthesis. Mice with targeted Scd1 gene deletion largely phenocopies Ire1α-deficient mice with diminished B-cell differentiation into plasma cells. Importantly, IRE1α expression and Xbp-1 mRNA splicing in B-cells from lupus patients are significantly increased, which positively correlate with the expression of both Scd1 and Scd2 genes, as well as with the amount of lipid deposition in B cells. Either genetic or pharmacological IRE1α suppression protected mice from lupus pathogenesis.

Conclusion: Our study reveals a molecular link of lipid metabolic dysregulation in lupus pathogenesis, demonstrates that the IRE1α-XBP-1 pathway controls plasma cell differentiation through SCD1/2-mediated monounsaturated fatty acid synthesis, and provides a rationale for targeting IRE1α and monounsaturated fatty acid synthesis in lupus treatment.

Keywords: B cell differentiation; IRE1α; Lupus; monounsaturated fatty acid; stearoyl-CoA desaturase 1.