在SPG11和SPG48中非正规炎症酶的过度活跃
Muhammad Awais Afzal1, Mohamed Ghait2, Adeela Hussain3
1Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747, Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747, Jena, Germany.
EBioMedicine
|October 25, 2025
概括
与SPG11突变相关的遗传性性 (HSP) 显示,由于非正规的炎症细胞超反应性,免疫细胞的炎症增加. 这有助于SPG11和SPG48.8中的神经炎症.
科学领域:
- 神经免疫学 神经免疫学
- 神经退行性疾病的遗传学
- 细胞生物学 细胞生物学
背景情况:
- 遗传性性 (HSP) 包括各种神经退行性步态障碍.
- SPG11基因变异导致最常见的自体逆向HSP,其产物Spatacsin与AP5.5相互作用.
- 在SPG11中的神经退行与显著的神经炎症有关,这表明Spatacsin在促炎细胞中的作用.
研究的目的:
- 为了研究Spatacsin在促炎细胞中的细胞自主作用.
- 探索斯帕塔素缺乏对炎症酶激活和炎症反应的影响.
- 确定先天性免疫细胞炎症酶过敏反应对SPG11和SPG48中神经炎症的贡献.
主要方法:
- 评估了原发性微质细胞,骨髓衍生的巨细胞 (BMDMs) 和来自野生类型,Spg11 KO和Ap5z1 KO小鼠的患者衍生的单细胞衍生的巨细胞 (MDMs) 的炎症酶激活.
- 在体内使用野生类型和Spg11KO小鼠研究了微质激活和脂多糖 (LPS) 诱导的炎症反应.
- 使用质谱法分析激活BMDM中的AP5亚单元表达.
主要成果:
- 在LPS挑战后,在症状前的Spg11 KO小鼠中,微质激活更为明显.
- Spg11 KO 微质和 BMDMs 通过非正规的炎症酶激活表现出更强烈的炎症反应,而正规通路没有受到影响.
- 来自SPG11患者的MDM显示了类似的发现;Spg11 KO小鼠在LPS后显示了炎症反应和死亡率的增加.
- Spg11的干扰导致AP5子单元的下调,而Ap5z1的干扰也使非正规的炎症体敏感.
结论:
- 天生的免疫细胞中的超反应性非正规性炎症酶对SPG11和SPG48.8中神经炎症有所贡献.
- 斯帕塔素缺乏影响AP5亚单元表达和炎症酶激活.
- 这些发现突出了SPG11和相关疾病的潜在治疗目标.
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