英国伦敦大学学院Claudia Mauri等研究人员合作发现，硫氧还蛋白是控制调节性B细胞的代谢变阻器。这一研究成果于2024年3月29日在线发表在国际学术期刊《自然—免疫学》上。

研究人员发现，与非调节性 B（B_reg）细胞不同，B_reg细胞的分化依赖于线粒体电子传递和活性氧（ROS）的平衡水平。单细胞RNA测序分析表明，编码代谢氧化还原蛋白硫氧化还原蛋白（Trx）的TXN基因在B_reg细胞中高度表达，而与之不同的是，Trx抑制剂TXNIP则呈下调状态。药理抑制或基因沉默TXN会导致线粒体膜去极化和ROS水平升高，从而选择性地抑制B_reg细胞的分化和功能，而有利于促炎性B细胞的分化。

以B_reg细胞缺乏为特征的系统性红斑狼疮（SLE）患者表现为B细胞线粒体膜去极化、ROS升高和Trx⁺ B细胞减少。外源性Trx刺激可使SLE B细胞中的B_reg细胞和线粒体膜极化恢复到健康B细胞的水平，这表明Trx不足是SLE患者B_reg细胞受损的原因。

据介绍，代谢编程对 B 细胞的命运很重要，但B_reg细胞分化和功能的生物能要求尚不清楚。

附：英文原文

Title: Thioredoxin is a metabolic rheostat controlling regulatory B cells

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

Issue&Volume: 2024-03-29

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

DOI: 10.1038/s41590-024-01798-w

Source: https://www.nature.com/articles/s41590-024-01798-w