Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Nat Immunol. 2018 Feb;19(2):151-161. doi: 10.1038/s41590-017-0021-y. Epub 2018 Jan 1.
Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, which suggests that viruses affect these processes. Here, in an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in the expression of genes encoding molecules that limit adult neurogenesis, including interleukin 1 (IL-1). Mice that had recovered from WNND exhibited fewer neuroblasts and increased astrogenesis without recovery of hippocampal neurogenesis at 30 d. Analysis of cytokine production in microglia and astrocytes isolated ex vivo revealed that the latter were the predominant source of IL-1. Mice deficient in the IL-1 receptor IL-1R1 and that had recovered from WNND exhibited normal neurogenesis, recovery of presynaptic termini and resistance to spatial learning defects, the last of which likewise occurred after treatment with an IL-1R1 antagonist. Thus, 'preferential' generation of proinflammatory astrocytes impaired the homeostasis of neuronal progenitor cells via expression of IL-1; this might underlie the long-term cognitive consequences of WNND but also provides a therapeutic target.
西尼罗河病毒神经侵袭性疾病（WNND）后记忆损伤与海马突触丧失和缺乏恢复有关。成人神经发生和突触发生是海马修复的基本特征，这表明病毒会影响这些过程。在这里，在WNND 诱导的认知功能障碍的既定模型中，转录谱分析显示，编码限制成人神经发生的分子的基因表达发生改变，包括白细胞介素 1（IL-1）。从 WNND 中恢复的小鼠在 30 天时表现出更少的神经母细胞和增加的星形胶质细胞增生，而没有海马神经发生的恢复。对离体分离的小胶质细胞和星形胶质细胞中细胞因子产生的分析表明，后者是 IL-1 的主要来源。从 WNND 中恢复的缺乏白细胞介素 1 受体 IL-1R1 的小鼠表现出正常的神经发生、突触前末端的恢复以及对空间学习缺陷的抵抗，后者在使用 IL-1R1 拮抗剂治疗后也会发生。因此，“优先”产生促炎星形胶质细胞通过表达 IL-1 损害神经元祖细胞的内稳态；这可能是 WNND 的长期认知后果的基础，但也提供了一个治疗靶点。
