Expansion of myeloid-derived suppressor cells with aging in the bone marrow of mice through a NF-κB-dependent mechanism.
Expansion of myeloid-derived suppressor cells with aging in the bone marrow of mice through a NF-κB-dependent mechanism.
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DOI：
10.1111/acel.12571
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发表时间：
2017-06
期刊：
影响因子：
7.8
通讯作者：
Robbins PD
中科院分区：
文献类型：
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作者：
Flores RR;Clauson CL;Cho J;Lee BC;McGowan SJ;Baker DJ;Niedernhofer LJ;Robbins PD
随着衰老，组织稳态和功能储备逐渐丧失，导致对压力的反应受损，发病和死亡的风险增加。细胞对损伤和应激反应的关键介质是转录因子 NF-κB。我们之前证明，在自然衰老小鼠的组织和由 DNA 损伤修复缺陷引起的人类早衰综合症小鼠模型（ERCC1 缺陷小鼠）的组织中，NF-κB 转录活性均上调。我们还证明，在加速衰老的 Ercc1 -/Δ 早衰小鼠模型中，NF-κB 亚基 p65(RelA) 水平的遗传降低可以延迟与年龄相关的病理学的发生，包括肌肉萎缩、骨质疏松和椎间盘退变。在此，我们报告老年（> 2 岁）小鼠（C57BL/6-NF-κBEGFP 报告小鼠）骨髓 (BM) 中最大部分的 NF-κB 表达细胞是 Gr-1+CD11b+骨髓源性抑制细胞 (MDSC)。与年轻动物相比，老年动物的 BM 中 MDSC 的总体百分比显着增加，在脾脏中也观察到了这一趋势。然而，这些细胞的功能在老年小鼠中似乎并未受到损害。在早衰 Ercc1 -/Δ 和 BubR1 H/H 小鼠的 BM 中观察到 MDSC 的类似增加。 Ercc1 -/Δ 小鼠中 MDSC 的增加被 NF-κB 的 p65/RelA 亚基的杂合性消除。这些结果表明，随着衰老，NF-κB 的激活至少在一定程度上会导致 MDSC（一种能够抑制免疫细胞反应的细胞类型）百分比的增加。
With aging, there is progressive loss of tissue homeostasis and functional reserve, leading to an impaired response to stress and an increased risk of morbidity and mortality. A key mediator of the cellular response to damage and stress is the transcription factor NF‐κB. We demonstrated previously that NF‐κB transcriptional activity is upregulated in tissues from both natural aged mice and in a mouse model of a human progeroid syndrome caused by defective repair of DNA damage (ERCC1‐deficient mice). We also demonstrated that genetic reduction in the level of the NF‐κB subunit p65(RelA) in the Ercc1 −/∆ progeroid mouse model of accelerated aging delayed the onset of age‐related pathology including muscle wasting, osteoporosis, and intervertebral disk degeneration. Here, we report that the largest fraction of NF‐κB ‐expressing cells in the bone marrow (BM) of aged (>2 year old) mice (C57BL/6‐NF‐κBEGFP reporter mice) are Gr‐1+CD11b+myeloid‐derived suppressor cells (MDSCs). There was a significant increase in the overall percentage of MDSC present in the BM of aged animals compared with young, a trend also observed in the spleen. However, the function of these cells appears not to be compromised in aged mice. A similar increase of MDSC was observed in BM of progeroid Ercc1 −/∆ and BubR1 H/H mice. The increase in MDSC in Ercc1 −/∆ mice was abrogated by heterozygosity in the p65/RelA subunit of NF‐κB. These results suggest that NF‐κB activation with aging, at least in part, drives an increase in the percentage of MDSCs, a cell type able to suppress immune cell responses.