Thioredoxin is a Metabolic Rheostat Controlling Regulatory B Cells

Overview

Journal Nat Immunol

Date 2024 Mar 30

PMID 38553615

Authors

Hannah F Bradford

Thomas C R McDonnell

Alexander Stewart

Andrew Skelton

Joseph Ng

Zara Baig

Franca Fraternali

Deborah Dunn-Walters

David A Isenberg

Adnan R Khan

Claudio Mauro

Claudia Mauri

Affiliations

Soon will be listed here.

Abstract

Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (B) cell differentiation and function is unknown. Here we show that B cell differentiation, unlike non-B 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 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 cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by B cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx B cells. Exogenous Trx stimulation restored B cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies B cell impairment in patients with SLE.

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