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Thioredoxin is a metabolic rheostat controlling regulatory B cells

2024; Nature Portfolio; Volume: 25; Issue: 5 Linguagem: Inglês

10.1038/s41590-024-01798-w

1529-2916

Hannah F. Bradford, Thomas McDonnell, Alexander Stewart, Andrew Skelton, Joseph Ng, Zara Baig, Franca Fraternali, Deborah K. Dunn‐Walters, David Isenberg, Adnan R. Khan, Claudio Mauro, Claudia Mauri,

interferon and immune responses

Abstract Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (B reg ) cell differentiation and function is unknown. Here we show that B reg cell differentiation, unlike non-B reg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN , encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by B reg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing B reg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by B reg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx + B cells. Exogenous Trx stimulation restored B reg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies B reg cell impairment in patients with SLE.