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缺氧诱导因子1α活性的动态调节对于正常B细胞发育至关重要
作者:小柯机器人 发布时间:2020/9/2 16:23:34

英国剑桥大学Natalie Burrows等研究人员发现,缺氧诱导因子1α活性的动态调节对于正常B细胞发育至关重要。 相关论文于2020年8月31日在线发表于《自然—免疫学》。

研究人员表示,B淋巴细胞的发育和选择对于适应性免疫和自我耐受至关重要。这些过程需要B细胞受体(BCR)信号,并发生骨髓中(具有不同缺氧程度的环境),但是尚不清楚是否涉及缺氧诱导因子(HIF)。
 
研究人员发现,人类和鼠类骨髓pro-B和pre-B细胞中的HIF活性很高,并且在未成熟的B细胞阶段降低。正常的B细胞发育需要这种阶段特异性的HIF抑制,因为鼠B细胞中HIF-1α的遗传激活会导致库多样性降低、BCR编辑减少以及未成熟B细胞发育停滞,从而导致外周B细胞数量减少。HIF-1α激活降低了表面BCR、CD19和B细胞激活因子受体,并增加了促凋亡BIM的表达。BIM的敲除挽救了发育障碍。在临床中使用HIF激活剂可显著减少骨髓和过渡性B细胞,这具有治疗意义。
 
总之,这些工作表明,HIF-1α的动态调节对于正常B细胞发育至关重要。
 
附:英文原文

Title: Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development

Author: Natalie Burrows, Rachael J. M. Bashford-Rogers, Vijesh J. Bhute, Ana Pealver, John R. Ferdinand, Benjamin J. Stewart, Joscelin E. G. Smith, Mukta Deobagkar-Lele, Girolamo Giudice, Thomas M. Connor, Akimichi Inaba, Laura Bergamaschi, Sam Smith, Maxine G. B. Tran, Evangelia Petsalaki, Paul A. Lyons, Marion Espeli, Brian J. P. Huntly, Kenneth G. C. Smith, Richard J. Cornall, Menna R. Clatworthy, Patrick H. Maxwell

Issue&Volume: 2020-08-31

Abstract: B lymphocyte development and selection are central to adaptive immunity and self-tolerance. These processes require B cell receptor (BCR) signaling and occur in bone marrow, an environment with variable hypoxia, but whether hypoxia-inducible factor (HIF) is involved is unknown. We show that HIF activity is high in human and murine bone marrow pro-B and pre-B cells and decreases at the immature B cell stage. This stage-specific HIF suppression is required for normal B cell development because genetic activation of HIF-1α in murine B cells led to reduced repertoire diversity, decreased BCR editing and developmental arrest of immature B cells, resulting in reduced peripheral B cell numbers. HIF-1α activation lowered surface BCR, CD19 and B cell–activating factor receptor and increased expression of proapoptotic BIM. BIM deletion rescued the developmental block. Administration of a HIF activator in clinical use markedly reduced bone marrow and transitional B cells, which has therapeutic implications. Together, our work demonstrates that dynamic regulation of HIF-1α is essential for normal B cell development.

DOI: 10.1038/s41590-020-0772-8

Source: https://www.nature.com/articles/s41590-020-0772-8

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex