The Biotherapy Center, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
Immunology. 2022 Dec;167(4):576-589. doi: 10.1111/imm.13554. Epub 2022 Aug 10.
Regulatory B cells (Bregs) are immune cells that constrain autoimmune response and restrict inflammation via their expression of interleukin (IL)-10. However, the molecular mechanisms underlying Breg differentiation and IL-10 secretion remain unclear. Previous data suggest that cellular metabolism determines both the fate and function of these cells. Here, we suggest an essential role for mitochondrial oxidative phosphorylation (OXPHOS) in the regulation of IL-10 in these Bregs. We found that IL-10 B cells from IL-10-green fluorescent protein-expressing mice had higher oxygen consumption rate than IL-10 B cells. In addition, inhibition of OXPHOS decreased the expression of IL-10 in B cells. Furthermore, suppression of OXPHOS diminished the expression of surface markers for Bregs and impaired their therapeutic effects in dextran sulphate sodium (DSS)-induced colitis. Mechanistically, mitochondrial OXPHOS was found to regulate the transcription factor HIF-1α through the extracellular signal-related kinase pathway. Taken together, this study reveals a strong correlation between mitochondrial OXPHOS and Breg phenotype/function, indicating OXPHOS as a therapeutic target in autoimmune diseases driven by Breg dysfunction.
调节性 B 细胞（Bregs）是通过表达白细胞介素（IL）-10 来限制自身免疫反应和炎症的免疫细胞。然而，Breg 分化和 IL-10 分泌的分子机制仍不清楚。先前的数据表明，细胞代谢决定了这些细胞的命运和功能。在这里，我们提出线粒体氧化磷酸化（OXPHOS）在调节这些 Bregs 中的 IL-10 方面起着重要作用。我们发现，来自表达 IL-10-绿色荧光蛋白的小鼠的 IL-10 B 细胞比 IL-10 B 细胞具有更高的耗氧率。此外，抑制 OXPHOS 会降低 B 细胞中 IL-10 的表达。此外，抑制 OXPHOS 会降低 Breg 表面标志物的表达，并损害其在葡聚糖硫酸钠（DSS）诱导的结肠炎中的治疗效果。从机制上讲，线粒体 OXPHOS 通过细胞外信号相关激酶途径调节转录因子 HIF-1α。总之，这项研究揭示了线粒体 OXPHOS 与 Breg 表型/功能之间的强烈相关性，表明 OXPHOS 是由 Breg 功能障碍驱动的自身免疫疾病的治疗靶点。
