Interleukin-3 Modulates Macrophage Phagocytic Activity and Promotes Spinal Cord Injury Repair

IF 5 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-12-19 DOI:10.1111/cns.70181

Jianjian Li, Meige Zheng, Fangru Ouyang, Jianan Ye, Jinxin Huang, Yuanzhe Zhao, Jingwen Wang, Fangli Shan, Ziyu Li, Shuishen Yu, Fei Yao, Dasheng Tian, Li Cheng, Juehua Jing

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Abstract

Background

Effective clearance of lipid-rich debris by macrophages is critical for neural repair and regeneration after spinal cord injury (SCI). Interleukin-3 (IL-3) has been implicated in programming microglia to cluster and clear pathological aggregates in neurodegenerative disease. Yet, the influence of IL-3 on lipid debris clearance post-SCI is not well characterized.

Methods

We established a mouse model of spinal cord compression injury to investigate the role of IL-3. Blockage of IL-3 was achieved through intrathecal delivery of an IL-3-neutralizing antibody, while IL-3 activation was augmented via in situ injection of recombinant IL-3 into the lesion site immediately post-SCI. Immunofluorescence staining was performed to determine IL-3 and IL-3Rα sources and distribution, lipid droplet accumulation, neuron preservation, and axon regeneration after SCI. The Basso Mouse Scale (BMS) and footprint analysis were employed to evaluate locomotor function recovery.

Results

We found that IL-3 expression was significantly upregulated post-SCI, peaking at 14 days post-injury (dpi) and persisting until 28 dpi. Notably, IL-3 was primarily secreted by astrocytes surrounding the lesion epicenter. Correspondingly, IL-3Rα was predominantly observed in macrophages within the injury core, also elevating at 14 dpi. Neutralization of IL-3 led to increased lipid droplet accumulation, along with markedly widespread of macrophages and decreased neuronal survival, resulting in severe motor deficits compared to controls. Conversely, in situ injection of IL-3 reduced lipid droplet accumulation in macrophages, preserved neurons, promoted axon regeneration, and ultimately contributed to the recovery of motor function after SCI.

Conclusion

Our findings shed light on the role of IL-3 in modulating macrophage phagocytic activity and suggest that the IL-3/IL-3Rα pathway may be a potential therapeutic target for enhancing neural repair and functional recovery after SCI.

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白细胞介素-3调节巨噬细胞吞噬活性并促进脊髓损伤修复。

背景：巨噬细胞有效清除富含脂质的碎片对于脊髓损伤（SCI）后神经修复和再生至关重要。在神经退行性疾病中，白细胞介素-3 （IL-3）参与编程小胶质细胞聚集和清除病理聚集。然而，IL-3对脊髓损伤后脂质碎片清除的影响尚不清楚。方法：建立小鼠脊髓压缩损伤模型，探讨IL-3在脊髓压缩损伤中的作用。通过鞘内递送IL-3中和抗体实现IL-3的阻断，而在脊髓损伤后立即在病变部位原位注射重组IL-3来增强IL-3的激活。免疫荧光染色检测脊髓损伤后IL-3和IL-3Rα的来源和分布、脂滴积累、神经元保存和轴突再生情况。采用Basso小鼠量表（BMS）和足迹分析法评估运动功能恢复情况。结果：我们发现IL-3的表达在脊髓损伤后显著上调，在损伤后14天达到峰值，并持续到28天。值得注意的是，IL-3主要由病变中心周围的星形胶质细胞分泌。相应的，IL-3Rα主要出现在损伤核心内的巨噬细胞中，也在14 dpi时升高。与对照组相比，IL-3的中和导致脂滴积累增加，巨噬细胞明显广泛分布，神经元存活减少，导致严重的运动缺陷。相反，原位注射IL-3可减少巨噬细胞内脂滴积聚，保存神经元，促进轴突再生，最终有助于脊髓损伤后运动功能的恢复。结论：我们的研究结果揭示了IL-3在调节巨噬细胞吞噬活性中的作用，并提示IL-3/IL-3Rα途径可能是增强脊髓损伤后神经修复和功能恢复的潜在治疗靶点。

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.