Fucoidan reduces NET accumulation and alleviates chemotherapy-induced peripheral neuropathy via the gut-blood-DRG axis.

IF 9.3 1区医学 Q1 IMMUNOLOGY

Journal of Neuroinflammation Pub Date : 2025-04-04 DOI:10.1186/s12974-025-03431-5

Rumeng Jia, Li Wan, Lai Jin, Qingyan Tian, Yongyi Chen, Xia Zhu, Mengyao Zhang, Yajie Zhang, Lijuan Zong, Xuefeng Wu, Chen Miao, Yihang Cai, Jianxin Ma, Liang Hu, Wen-Tao Liu

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引用次数: 0

Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse reaction to chemotherapy with limited treatment options. Research has indicated that neutrophil extracellular traps (NETs) are critical for the pathogenesis of CIPN. LPS/HMGB1 serve as important inducers of NETs. Here, we aimed to target the inhibition of NET formation (NETosis) to alleviate CIPN.

Methods: Oxaliplatin (L-OHP) was used to establish a CIPN model. The mice were pretreated with fucoidan to investigate the therapeutic effect. SR-A1^-/- mice were used to examine the role of scavenger receptor A1 (SR-A1) in CIPN. Bone marrow-derived macrophages (BMDMs) isolated from SR-A1^-/- mice and WT mice were used to investigate the mechanism by which macrophage phagocytosis of NETs alleviates CIPN.

Results: Clinically, we found that the contents of LPS, HMGB1 and NETs in the plasma of CIPN patients were significantly increased and positively correlated with the VAS score. Fucoidan decreased the LPS/HMGB1/NET contents and relieved CIPN in mice. Mechanistically, fucoidan upregulated SR-A1 expression and promoted the phagocytosis of LPS/HMGB1 by BMDMs. Fucoidan also facilitated the engulfment of NETs by BMDMs via the recognition and localization of SR-A1 and HMGB1. The therapeutic effects of fucoidan were abolished by SR-A1 knockout. RNA-seq analysis revealed that fucoidan increased sqstm1 (p62) gene expression. Fucoidan promoted the competitive binding of sqstm1 and Nrf2 to Keap1, increasing Nrf2 nuclear translocation and SR-A1 transcription. Additionally, the sequencing analysis (16 S) of microbial diversity revealed that fucoidan increased the gut microbiota diversity and abundance and increased the Bacteroides/Firmicutes ratio.

Conclusions: Altogether, fucoidan promotes the SR-A1-mediated phagocytosis of LPS/HMGB1/NETs and maintains gut microbial homeostasis, which may provide a potential therapeutic strategy for CIPN.

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岩藻糖聚糖通过肠-血- drg轴减少NET积累，减轻化疗引起的周围神经病变。

背景：化疗引起的周围神经病变（CIPN）是化疗的严重不良反应，治疗方案有限。研究表明，中性粒细胞胞外陷阱（NETs）对CIPN的发病机制至关重要。LPS/HMGB1是NETs的重要诱导剂。在这里，我们的目标是抑制NET的形成（NETosis）来减轻CIPN。方法：采用奥沙利铂（L-OHP）建立CIPN模型。用褐藻糖聚糖预处理小鼠，观察其治疗效果。用SR-A1-/-小鼠检测清道夫受体A1 （SR-A1）在CIPN中的作用。采用SR-A1-/-小鼠和WT小鼠分离的骨髓源性巨噬细胞（bmmdms），探讨NETs巨噬细胞吞噬减轻CIPN的机制。结果：临床我们发现CIPN患者血浆中LPS、HMGB1、NETs含量明显升高，且与VAS评分呈正相关。褐藻多糖降低LPS/HMGB1/NET含量，减轻小鼠CIPN。在机制上，褐藻聚糖上调SR-A1的表达，促进脂多糖对LPS/HMGB1的吞噬。岩藻聚糖还通过SR-A1和HMGB1的识别和定位促进了BMDMs对NETs的吞噬。敲除SR-A1后，褐藻糖聚糖的治疗作用消失。RNA-seq分析显示褐藻聚糖增加了sqstm1 （p62）基因的表达。褐藻多糖促进sqstm1和Nrf2与Keap1的竞争性结合，增加Nrf2核易位和SR-A1转录。此外，微生物多样性测序分析（16s）显示，岩藻聚糖增加了肠道微生物群的多样性和丰度，提高了拟杆菌/厚壁菌门的比例。结论：岩藻糖聚糖促进sr - a1介导的LPS/HMGB1/NETs的吞噬，维持肠道微生物稳态，可能为CIPN提供潜在的治疗策略。

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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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.