c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.
c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.
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c-Myc 驱动的糖酵解使功能性调节 B 细胞极化，从而触发致病反应
DOI：
10.1038/s41392-022-00948-6
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发表时间：
2022-04-18
影响因子：
39.3
通讯作者：
Chen, Yun
中科院分区：
文献类型：
--
作者：
Wang, Xu-Yan;Wei, Yuan;Hu, Bo;Liao, Yuan;Wang, Xiaodong;Wan, Wen-Hua;Huang, Chun-Xiang;Mahabati, Mahepali;Liu, Zheng-Yu;Qu, Jing-Rui;Chen, Xiao-Dan;Chen, Dong-Ping;Kuang, Dong-Ming;Wang, Xue-Hao;Chen, Yun
功能性分泌 IL-10 的 B 细胞被认为是功能性调节 B (Breg) 细胞；然而，关于人类分泌 IL-10 的 Breg 细胞的表型、调节以及功能和临床相关性的直接证据仍然缺乏。在这里，我们证明，虽然 IL-10 本身具有抗炎作用，但系统性红斑狼疮 (SLE) 患者的 IL-10+ 功能性 Breg 细胞表现出侵袭性炎症特征；这些特征使它们的功能不再诱导 CD8+ T 细胞耐受，而是诱导致病性 CD4+ T 细胞反应。由环境因素（例如 CPG-DNA）极化或直接从 SLE 患者分离的功能性 Breg 细胞主要表现出与其前体不同的 CD24intCD27−CD38−CD69+/hi 表型。从机制上讲，MAPK/ERK/P38 引发的连续致癌 c-Myc 上调和糖酵解增强对于功能性 Breg 细胞的生成和功能维持是必要的。一致地，消除 ERK、P38、c-Myc 和/或细胞糖酵解活性的策略可以有效消除功能性 Breg 细胞引发的致病作用。
B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8+ T cell tolerance and cause them to induce a pathogenic CD4+ T cell response. Functional Breg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24intCD27−CD38−CD69+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional Breg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional Breg cells.
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