中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (5): 817-825.doi: 10.4103/1673-5374.249229

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

脂多糖诱导神经炎症对成体海马神经发生不利影响取决于促炎反应的持续时间

  

  • 出版日期:2019-05-15 发布日期:2019-05-15
  • 基金资助:

    墨西哥研究项目和技术创新支持计划（PAPIIT）和国家科学技术委员会基金

The detrimental effects of lipopolysaccharide-induced neuroinflammation on adult hippocampal neurogenesis depend on the duration of the pro-inflammatory response

Martha Pérez-Domínguez  , Evangelina Ávila-Muñoz, Eduardo Domínguez-Rivas, Angélica Zepeda   

  1. Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México, CDMX, México
  • Online:2019-05-15 Published:2019-05-15
  • Contact: Martha Pérez-Domínguez, marthaperezd@comunidad.unam.mx
  • Supported by:

    This work was supported by grants from Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica: 203015, 208518, and Consejo Nacional de Ciencia y Tecnología (CONACyT): 282470.

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摘要：

在动物模型中，脂多糖诱导的神经炎症主要与早期炎症反应相关的神经源性降低有关。然而，尚不清楚神经炎症反应如何随时间推移以及成体神经发生在晚期神经炎症反应期间是否继续减弱尚不清楚。此外，尚不知脂多糖的重复间歇给药是否会导致神经发生更大程度的减弱。为了解答这些问题，实验给年轻成年小鼠施用单次或4次（每周1次）重复腹腔内注射脂多糖或生理盐水。在最后一次脂多糖注射后4d，以5-溴-2-脱氧尿苷标记新生神经细胞。结果显示：（1）单次脂多糖注射导致晚期促炎反应，其特征在于小胶质细胞激活，中度星形胶质细胞反应和增加的白细胞介素6水平，该反应在时间上与神经发生减弱相关；（2）重复间歇注射脂多糖不会引起晚期促炎反应，尽管活化的小胶质细胞持续存在，但其并未伴随持续的长期海马神经发生减弱。实验提供的证据表明，神经炎症反应是一个动态过程，其持续进展并不一定导致神经发生减弱。

orcid:  0000-0003-2235-3328 (Martha Pérez-Domínguez)

关键词: 齿状回, 颗粒下层, 炎症, 小胶质细胞, 星形胶质细胞, 白细胞介素6, 细胞因子, 细胞增殖, 神经祖细胞, 未成熟神经元, 成体神经发生, 神经再生

Abstract:

Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide (LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections (one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections (one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued long-term hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.

Key words: dentate gyrus, subgranular zone, inflammation, microglia, astrocytes, IL-6, cytokines, cell proliferation, neural progenitor cells, immature neurons, long-term, short-term, adult hippocampal neurogenesis