The brain-bone marrow axis and its implications for chronic traumatic brain injury.

Rodney M Ritzel, Yun Li, Yun Jiao, Sarah J Doran, Niaz Khan, Rebecca J Henry, Kavitha Brunner, David J Loane, Alan I Faden, Gregory L Szeto, Junfang Wu
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Abstract

Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.

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脑骨髓轴:对慢性创伤性脑损伤和年龄相关神经退行性变的影响。
引言:众所周知,创伤性脑损伤(TBI)会导致系统免疫功能的急性和慢性改变,而系统免疫变化会导致创伤后神经炎症和神经退行性变。然而,TBI如何长期影响骨髓(BM)造血干细胞/祖细胞,以及这种变化在多大程度上可能对先天免疫和神经功能产生负面影响,尚未得到研究。方法:为了进一步了解骨髓细胞衍生物对TBI结果的作用,我们通过将慢性损伤或假手术(即手术后90天)的骨髓移植到健康、年龄匹配、受辐射的宿主中,产生了骨髓嵌合小鼠。通过流式细胞术、多重ELISA和NanoString技术评估免疫变化。中度至重度TBI由可控的皮层撞击损伤诱导,神经功能使用一组行为测试进行测量。结果:TBI在野生型(WT)小鼠中诱导BM谱系-c-Kit+Sca1+(LSK+)细胞转录组的慢性改变,包括改变的表观遗传和衰老途径。重建8周后,在TBI中未观察到BM或血白细胞数量或组成的变化→WT嵌合小鼠与任一SH的比较→WT或未经照射的WT对照小鼠,提示正常植入。然而,来自TBI的外周骨髓细胞→WT小鼠表现出显著更高的氧化应激水平和降低的吞噬活性,这与之前在WT TBI小鼠中的发现一致。TBI→WT小鼠也表现出较高的趋化因子血浆浓度,并表现出显著的神经功能缺陷。重建后8个月,TBI→WT嵌合小鼠是白细胞减少的,具有持续改变的吞噬作用和氧化应激反应,以及持续的神经功能缺陷。NanoString基因表达分析显示,分别在重建8周和8个月后,BM驱动的神经炎症和神经病理学变化。重组后8周和8个月接受TBI的嵌合小鼠显示,较长的重组期(即损伤后的时间)与小胶质细胞增多和白细胞浸润有关。用解氨剂ABT-263预处理,在基线时显著改善了老年小鼠的行为表现,尽管它没有减轻急性损伤大脑中的神经炎症。结论:TBI导致骨髓干/祖细胞库的慢性激活和进行性功能障碍,导致造血、先天免疫、神经功能的长期缺陷,以及对随后脑损伤的敏感性改变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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