亨廷顿病患者外周血和中枢IL-8升高

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology Pub Date : 2025-02-10 DOI:10.1016/j.molimm.2025.02.003

Jenny N. Fung , John D. Lee , Robert Adam , John D. O’Sullivan , Trent M. Woodruff

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引用次数: 0

摘要

目的亨廷顿氏病（HD）是一种以运动、认知和精神异常为特征的衰弱性神经退行性疾病。免疫功能亢进和失调在HD中很常见。除中枢神经系统外，HD患者还表现出全身性先天免疫激活和炎症，这已被证明是亨廷顿基因突变的致病因素之一。在动物亨廷顿病模型中观察到包括干扰素γ (IFN-γ)和白细胞介素(IL)-8在内的炎症介质的上调。然而，对HD患者的研究仍然有限。方法在本研究中，使用基于头部的分析方法分析了58例HD患者和59例年龄和性别匹配的健康对照者的血清样本，该方法可以同时测量13种细胞因子和趋化因子。此外，对HD患者和对照组脑组织的公开转录组学数据进行了检查。我们的研究结果证实，与非HD对照组相比，HD患者的IL-8蛋白水平显著升高，中度HD组的IL-8蛋白水平最高。在对照组中，我们发现IL-8水平与IL-17A和IL-10之间存在显著正相关。然而，在HD患者中没有观察到这些相关性，其中IL-8水平与促炎标志物（包括IFNγ和IL-23）显着正相关。有趣的是，IL-17A水平与疾病参数呈负相关，包括CAG三核苷酸重复扩增和疾病负担评分。此外，细胞因子和趋化因子如IFNγ和单核细胞趋化蛋白1 (MCP-1；CCL2)与相同的疾病参数呈正相关。对公开的大量RNAseq和单核rna测序（snRNAseq）数据的深入分析显示，与非HD对照相比，HD患者皮质样品中的IL-8表达显著增加。此外，纹状体中的snRNAseq数据显示，HD患者的IL-8表达高于非HD对照组，主要表达在小胶质细胞中。总的来说，我们的研究结果支持HD患者IL-8的上调，在中枢退行性脑区和外周血样本中都很明显。我们确定了与HD严重程度相关的独特免疫特征，并提供了可能反映HD患者免疫病理机制的潜在生物标志物。

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Peripheral and central elevation of IL-8 in patients with Huntington’s disease

Objectives

Huntington’s Disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune hyperactivity and dysregulation are common in HD. In addition to the central nervous system, HD patients exhibit systemic innate immune activation and inflammation, which has been shown to contribute to the pathogenic effects of the Huntingtin gene mutation. Upregulation of inflammatory mediators including interferon gamma (IFN-γ) and interleukin (IL)-8 has been observed in animal Huntington’s disease models. However, studies on HD patients remain limited.

Methods

In this study, serum samples from 58 HD patients and 59 age- and gender-matched healthy control individuals were analysed using a bead-based assay, that enabled simultaneous measurement of 13 cytokines and chemokines. Additionally, publicly available transcriptomic data from brain tissues of HD patients and controls were examined.

Results

Our results confirm that IL-8 protein levels are significantly higher in HD patients compared to non-HD controls, with the highest levels observed in the moderate HD group. In the control group, we found significant positive correlations between IL-8 levels and both IL-17A and IL-10. However, these correlations were not observed in HD patients, where IL-8 levels were notably positively correlated with pro-inflammatory markers including IFNγ and IL-23. Interestingly, IL-17A levels demonstrated a negative correlation with disease parameters, including CAG trinucleotide repeat expansion and disease burden score. Furthermore, cytokines and chemokines such as IFNγ and monocyte chemoattractant protein 1 (MCP-1; CCL2) demonstrated positive correlations with the same disease parameters. In-depth analysis of publicly available bulk RNAseq, and single-nucleus RNA-sequencing (snRNAseq) data from two key HD-affected brain regions- the prefrontal cortex and striatum revealed that IL-8 expression is significantly increased in cortex samples from individuals with HD compared to non-HD controls. Moreover, snRNAseq data in the striatum showed higher IL-8 expression in HD patients than in non-HD controls, with a predominant expression in microglia.

Conclusion

Overall, our findings support an upregulation of IL-8 in patients with HD, evident in both central degenerating brain regions, and peripheral blood samples. We identified unique immunological signatures associated with the severity of HD and provide potential biomarkers that may reflect immune-pathological mechanisms in HD patients.

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.