髓细胞中的星形胶质细胞升高基因-1 (AEG-1)是化疗诱导周围神经病变发展的关键驱动因素。

IF 8.8 2区 医学 Q1 IMMUNOLOGY
Bryan D. Mckiver , Sara M. Herz , Shivani Patel , Tayla Bryan , Jared Mann , Justin L. Poklis , John W. Bigbee , Jolene J. Windle , Aliasger K. Salem , Devanand Sarkar , M.Imad Damaj
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引用次数: 0

摘要

化疗引起的周围神经病变(CIPN)是化疗的一种剂量限制性副作用,通常导致停止治疗。紫杉醇激活外周巨噬细胞,产生神经炎症反应,促进CIPN的发展和维持。星形胶质细胞升高基因-1 (AEG-1),也称为Metadherin或LYRIC,是一种多功能蛋白,通过与NF-κB(促炎细胞因子/趋化因子(PIC)表达的转录调节因子)的直接相互作用,调节巨噬细胞活性并调节炎症。我们的目的是通过在复制特定人类临床表型的CIPN动物模型中使用全局(AEG-1 KO)和髓细胞特异性敲除(AEG-1ΔMAC)转基因小鼠菌株,确定AEG-1是否有助于CIPN病理的发展和维持。我们假设抑制髓系细胞(如单核细胞和巨噬细胞)中AEG1的表达会阻止CIPN的发展和维持。我们的研究结果表明,全局AEG-1缺失阻止了PAC和奥沙利铂(OHP)诱导的CIPN病理的发展。研究发现,PAC处理可增加WT小鼠DRGs和C57BL/6J小鼠腹腔巨噬细胞中AEG-1和PIC的表达。然而,在没有AEG-1表达的情况下,pac诱导的神经炎症在AEG-1 KO小鼠的DRGs中完全停止。这种预防性表型和PIC表达谱在AEG-1ΔMAC小鼠中也得到了反映,在PAC治疗后,它们也显示出NF-κB蛋白水平降低,F4/80+巨噬细胞被输送到腰椎DRGs。总之,我们的研究结果首次证明了AEG-1在CIPN发展中的生物学作用,特别是在髓系细胞中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Astrocyte elevated gene-1 (AEG-1) in myeloid cells is a key driver for the development of chemotherapy-induced peripheral neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment. Paclitaxel activates peripheral macrophages, generating a neuroinflammatory response that contributes to CIPN development and maintenance.
Astrocyte Elevated Gene-1 (AEG-1), also known as Metadherin or LYRIC, is a multifunctional protein that modulates macrophage activity and regulates inflammation through direct interaction with NF-κB, a transcriptional regulator of proinflammatory cytokine/chemokine (PIC) expression.
We aimed to determine whether AEG-1 contributes to the development and maintenance of CIPN pathologies by using both global (AEG-1 KO) and myelocyte-specific knockout (AEG-1ΔMAC) transgenic mouse strains in an animal model of CIPN that replicates specific human clinical phenotypes. We hypothesized that inhibition of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the development and maintenance of CIPN.
Our results showed that global AEG-1 deletion prevented the development of CIPN pathologies induced by PAC, as well as oxaliplatin (OHP). PAC treatment was found to increase AEG-1 and PIC expression in the DRGs of WT mice and in peritoneal macrophages isolated from C57BL/6J mice. However, in the absence of AEG-1 expression, PAC-induced neuroinflammation was completely halted in the DRGs of AEG-1 KO mice. This preventative phenotype and PIC expression profile was mirrored in AEG-1ΔMAC mice, which also displayed reduced NF-κB protein levels and F4/80+ macrophages trafficked to the lumbar DRGs following PAC treatment.
In summary, our results are the first to demonstrate the biological role AEG-1, particularly in myeloid cells, in development of CIPN.
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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