Bcl11a maintains hematopoietic stem cell function but accelerates inflammation-driven exhaustion during aging

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-04-11 DOI:10.1126/sciimmunol.adr2041

Jing Wang, Linlin Zhang, Xinyu Cui, Xiang Xu, Rui Guo, Kairui Li, Li Zhang, Bing Xu, Cizhong Jiang, Yong Yu

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引用次数: 0

Abstract

Preserving hematopoietic stem cell (HSC) functionality is essential for maintaining healthy blood and the immune system throughout life. HSC function declines with age; however, the underlying mechanisms are not fully understood. Using an inducible mosaic mouse model to overexpress the transcription factor Bcl11a in the hematopoietic compartment, we found that an aging-related increase in Bcl11a mitigated HSC functional decline, promoted IL-1β production in the bone marrow (BM), and accelerated HSC attrition in a non–cell-autonomous manner. Aging-related inflammation in the BM enhanced Bcl11a and Fc receptor (FcR) expression in HSCs, and FcR signaling induced HSC differentiation. This was counteracted by Bcl11a through repression of Fcer1g. Bcl11a up-regulation promoted IL-1β production in BM myeloid cells, driving inflammation and HSC deterioration. Deletion of Fcer1g, or blocking IL-1β signaling, eliminated this non–cell-autonomous effect on HSC decline. These findings demonstrate that Bcl11a plays a dual role in HSCs during aging not only by cell-intrinsically preserving HSC function but also by promoting BM inflammation and HSC dysfunction.

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保持造血干细胞（HSC）的功能对于终生维持健康的血液和免疫系统至关重要。造血干细胞的功能会随着年龄的增长而下降，但其潜在机制尚未完全明了。我们利用诱导镶嵌小鼠模型在造血区系中过表达转录因子Bcl11a，发现与衰老相关的Bcl11a增加可减轻造血干细胞功能的衰退，促进骨髓（BM）中IL-1β的产生，并以非细胞自主的方式加速造血干细胞的损耗。BM中与衰老相关的炎症增强了造血干细胞中Bcl11a和Fc受体（FcR）的表达，FcR信号诱导了造血干细胞的分化。Bcl11a通过抑制Fcer1g抵消了这一作用。Bcl11a的上调促进了BM髓系细胞中IL-1β的产生，推动了炎症和造血干细胞的恶化。删除Fcer1g或阻断IL-1β信号传导可消除这种对造血干细胞衰退的非细胞自主效应。这些研究结果表明，Bcl11a在造血干细胞衰老过程中扮演着双重角色，它不仅能通过细胞内在作用保护造血干细胞功能，还能通过促进基质膜炎症和造血干细胞功能障碍发挥作用。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.