Bilirubin Alleviates Spinal Cord Injury by Enhancing SOCS3-Mediated Anti-Inflammatory Effects via Gas6-Axl Signaling

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-09-17 DOI:10.1111/cns.70538

Kun-Mao Jiang, Ya-Qi Luan, Na Shen, Xiu-Ting Qi, Liang Hu, Yu Wang, Wen-Tao Liu, Rong Wang, Tong-Tong Lin, Da-Yong Peng

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Abstract

Background

Many studies have emphasized the role of microglia-mediated neuroinflammation in spinal cord injury (SCI); however, effective clinical targets remain elusive. The growth arrest-specific 6 (Gas6)/Axl receptor tyrosine kinase (Axl) signaling pathway has been implicated in reducing inflammation, promoting tissue repair, and functional recovery. Here, we elucidate the importance of the Gas6-Axl signaling pathway in SCI repair and evaluate the role of bilirubin in modulating Gas6-Axl signaling after SCI.

Methods

SCI mice model was used to investigate the effects of bilirubin treatment on inflammation and motor function recovery. Additionally, Gas6-deficient (Gas6⁻/⁻) mice and wild-type (WT) mice were employed to examine the role of Gas6-Axl signaling in SCI recovery. Microglial cells were cultured to assess the effects of bilirubin on the activation of the Gas6-Axl-SOCS3 signaling pathway.

Results

Gas6⁻/⁻ mice exhibited increased mortality, severe locomotor deficits, and impaired neuromuscular activity compared to WT mice. Bilirubin treatment in SCI models facilitated recovery by upregulating Gas6-Axl signaling, which in turn enhanced SOCS3 expression and suppressed the expression of pro-inflammatory mediators such as IL-1β and MMP-9. Furthermore, bilirubin treatment reduced microglial activation, highlighting its neuroprotective and anti-inflammatory properties.

Conclusions

This study underscores the importance of the Gas6-Axl-SOCS3 axis in regulating functional recovery and inflammation after SCI. Activation of the Gas6-Axl pathway, particularly when combined with bilirubin treatment, represents a promising therapeutic strategy for mitigating SCI-induced damage and improving functional outcomes. Given their central role in both the pathogenesis and resolution of SCI, bilirubin treatment emerges as a promising clinical therapeutic drug for SCI.

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胆红素通过Gas6-Axl信号通路增强socs3介导的抗炎作用减轻脊髓损伤

背景：许多研究强调了小胶质细胞介导的神经炎症在脊髓损伤（SCI）中的作用；然而，有效的临床靶点仍然难以捉摸。生长阻滞特异性6 (Gas6)/Axl受体酪氨酸激酶（Axl）信号通路与减少炎症、促进组织修复和功能恢复有关。在此，我们阐明了Gas6-Axl信号通路在脊髓损伤修复中的重要性，并评估了胆红素在脊髓损伤后调节Gas6-Axl信号通路中的作用。方法：采用脊髓损伤小鼠模型，观察胆红素治疗对炎症及运动功能恢复的影响。此外，利用Gas6-缺失（Gas6-/-）小鼠和野生型（WT）小鼠来研究Gas6- axl信号在脊髓损伤恢复中的作用。培养小胶质细胞，评估胆红素对Gas6-Axl-SOCS3信号通路激活的影响。结果：与WT小鼠相比，Gas6-/-小鼠表现出更高的死亡率、严重的运动缺陷和神经肌肉活动受损。胆红素治疗通过上调Gas6-Axl信号通路促进脊髓损伤模型的恢复，从而增强SOCS3的表达，抑制IL-1β和MMP-9等促炎介质的表达。此外，胆红素治疗降低了小胶质细胞的激活，突出了其神经保护和抗炎特性。结论：本研究强调了Gas6-Axl-SOCS3轴在脊髓损伤后功能恢复和炎症调节中的重要性。激活Gas6-Axl通路，特别是与胆红素联合治疗时，代表了减轻sci诱导的损伤和改善功能结果的有希望的治疗策略。鉴于胆红素在脊髓损伤的发病机制和治疗中所起的核心作用，胆红素治疗成为一种很有前景的脊髓损伤临床治疗药物。

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

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.