Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system
Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system
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DOI：
10.1096/fj.05-3776fje
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发表时间：
2005-05-01
期刊：
影响因子：
4.8
通讯作者：
Johnson, RW
中科院分区：
文献类型：
--
作者：
Godbout, JP;Chen, J;Johnson, RW
急性认知障碍（即，谵妄）在老年急诊科患者中很常见，并且经常由与中枢神经系统无关的感染引起。由于外周先天免疫系统的激活诱导脑小胶质细胞产生导致行为缺陷的炎性细胞因子，我们研究了外周注射脂多糖（LPS）后衰老是否会加剧神经炎症和疾病行为。微阵列分析揭示了一个转录谱，表明在老年大脑中存在引发或激活的小胶质细胞和增加的炎症。此外，老年小鼠在腹腔内注射LPS后大脑中具有独特的基因表达谱，与成年小鼠相比，LPS诱导的脑炎性细胞因子和氧化应激的升高被夸大和延长。外周LPS给药后，老年小鼠的厌食时间更长，体重减轻更多。此外，运动和社会行为的减少仍然在老年小鼠24小时后，当成年人已经完全恢复，并在老年小鼠夸大的神经炎症反应是不可靠的周围循环细胞因子增加。综上所述，这些数据证实，与成年小鼠相比，外周先天免疫系统的激活导致老年小鼠的神经炎症加剧。外周和中枢先天免疫系统之间的这种失调联系可能与老年全身感染患者经常发生的严重行为缺陷有关。
Acute cognitive impairment (i.e., delirium) is common in elderly emergency department patients and frequently results from infections that are unrelated to the central nervous system. Since activation of the peripheral innate immune system induces brain microglia to produce inflammatory cytokines that are responsible for behavioral deficits, we investigated if aging exacerbated neuroinflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS). Microarray analysis revealed a transcriptional profile indicating the presence of primed or activated microglia and increased inflammation in the aged brain. Furthermore, aged mice had a unique gene expression profile in the brain after an intraperitoneal injection of LPS,and the LPS-induced elevation in the brain inflammatory cytokines and oxidative stress was both exaggerated and prolonged compared with adults. Aged mice were anorectic longer and lost more weight than adults after peripheral LPS administration. Moreover, reductions in both locomotor and social behavior remained 24 h later in aged mice, when adults had fully recovered, and the exaggerated neuroinflammatory response in aged mice was not reliably paralleled by increased circulating cytokines in the periphery. Taken together, these data establish that activation of the peripheral innate immune system leads to exacerbated neuroinflammation in the aged as compared with adult mice. This dysregulated link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections.