调控IL-17A/IL-17R通路对脓毒症小鼠远期认知功能的作用

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摘要目的探讨调控IL-17A/IL-17R通路对脓毒症小鼠远期认知功能的作用。方法采用盲肠结扎穿孔法(CLP)构建脓毒症小鼠模型。第一部分:将实验动物分为6组, 假手术(Sham)组,CLP 7、9、12、14、28 d各一组,每组5只。ELISA法检测白介素(IL)-17A、肿瘤坏死因子(TNF)-α、IL-β,免疫荧光检测Iba-1、CD11b,跳台实验和旷场实验测定小鼠认知功能。第二部分:将80只小鼠分为CLP 14 d脑室注射组和CLP 28 d脑室注射组,再将上述两组各自分为Sham组、CLP组、Sham+IL-17A组、CLP+IL-17A组、CLP+anti-IL-17A组、CLP+IsotypeA组、CLP+anti-IL-17R组、CLP+IsotypeB组,每组5只,按照分组分别用重组IL-17A、抗IL-17A抗体、抗IL-17R抗体、对应同型对照抗体或生理盐水预处理,然后检测小鼠认知功能变化、小胶质细胞活化水平及促炎细胞因子水平,检测方法同第一部分。结果第一部分研究表明,CLP7d与Sham组比较炎症因子(IL-17A、TNF-α、IL-1β)水平明显升高,中央穿格数、水平穿格数减少,记忆潜伏期缩短,认知功能明显受损,CLP 7～28 d炎症因子水平(IL-17A、TNF-α、IL-1β)缓慢增高,中央穿格数、水平穿格数有所减少,记忆潜伏期缩短,认知功能继续下降。第二部分研究数据表明,注射IL-17A的CLP14 d和28 d组较CLP组炎症因子(TNF-α、IL-1β)水平明显升高,中央穿格数、水平穿格数有所减少,记忆潜伏期缩短,认知功能明显受损;而注射anti-IL-17A/17R的CLP14 d和28 d组炎症因子(TNF-α、IL-1β)水平明显下降,中央穿格数、水平穿格数有所增加,记忆潜伏期延长,认知功能明显改善,各组差异有统计学意义(P<0.05)。结论脓毒症时脑组织匀浆内IL-17A水平变化与脓毒症小鼠远期认知功能障碍发生有关;干预IL-17A/IL-17R途径可抑制小胶质细胞活化,减轻脑内的免疫炎症反应,从而缓解脓毒症小鼠远期认知功能障碍。

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	董佳欣
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关键词 ：脓毒症相关性脑病, 小胶质细胞, 白细胞介素17A, 白细胞介素17受体, 中枢神经系统炎症, 远期认知功能

Abstract：Objective To explore the effect of regulating IL-17A/IL-17R pathway on long-term cognitive function in mice with sepsis. Methods A mouse model of sepsis was established by cecal ligation and perforation (CLP)In the first part,the experimental mice was divided of 6 groups, SHAM, CLP7, CLP12, CLP9,CLP14,CLP28d, with 5 mice in each group. IL-17A, TNF-α, IL-β were determined by ELISA,Iba-1 and CD11b were detected by immunofluorescence, and the cognitive function of mice was measured by jump test and open field test. In the second part, 80 mice were divided into CLP 14 day intraventricular injection group and CLP 28 day intraventricular injection group. Then the two groups were divided into Sham group, CLP group, Sham+IL-17A group, CLP+IL-17A group, CLP+anti-IL-17A group, CLP+IsotypeA group, CLP+anti-IL-17R group and CLP+IsotypeB group, with 5 animals in each group. According to the groups, the mice were pretreated with recombinant IL-17A, anti-IL-17A antibody, anti-IL-17R antibody, corresponding homologous control antibody or normal saline, and then the changes of cognitive function, the activation level of microglia cells and the levels of pro-inflammatory cytokines were detected. The detection method was the same as that in the first part. Results The first part of the study showed that the levels of inflammatory factors (IL-17A, TNF-α, IL-1β) significantly increased in CLP7d group compared with SHAM group, and the number of central and horizontal crossing grids decreased, the memory latency was shortened, and the cognitive function was significantly impaired. The levels of inflammatory factors (IL-17A, TNF-α, IL-1β) slowly increased from 7 to 28 days, the number of central and horizontal crossing grids decreased, the memory latency was shortened, and the cognitive function continued to decline. The second part showed that compared with CLP group, the levels of inflammatory factors (TNF-α, IL-1β) in CLP14 d and 28 d groups injected with IL-17A significantly increased the number of central and horizontal crossing grids decreased, the memory latency was shortened, and the cognitive function was significantly impaired. However, the levels of inflammatory factors (TNF-α, IL-1β) in CLP14 d and 28 d groups after anti-IL-17A/17R injection significantly decreased, the number of central and horizontal crossing grids increased, the memory latency was prolonged, and the cognitive function was significantly improved, with statistically significant differences among all the groups (P<0.05). Conclusions The level of IL-17A in brain homogenate during sepsis is related to the long-term cognitive dysfunction of sepsis mice. Intervention of IL-17A/IL-17R pathway can inhibit the activation of microglia and reduce the immune inflammatory response in the brain, thereby improving the long-term cognitive dysfunction of sepsis mice.

Key words： sepsis-associated encephalopathy microglia interleukin 17A interleukin 17 receptor neuroinflammation long-term cognition function

收稿日期: 2023-09-25

ZTFLH:

R59

基金资助:科技助推项目(2022ZTYB44,2022ZTYB38)

通讯作者: 叶博,E-mail:miatnight@163.com

作者简介: 董佳欣,硕士,住院医师。

引用本文:

董佳欣, 陶天柱, 杨晓明, 何笑菲, 叶博. 调控IL-17A/IL-17R通路对脓毒症小鼠远期认知功能的作用[J]. 武警医学, 2024, 35(4): 312-317. DONG Jiaxin, TAO Tianzhu, YANG Xiaoming, HE Xiaofei, YE Bo. Effects of regulating IL-17A/IL-17R pathway on long-term cognitive function in mice with sepsis. Med. J. Chin. Peop. Armed Poli. Forc., 2024, 35(4): 312-317.

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http://journal08.magtechjournal.com/Jwk_wjyx/CN/ 或 http://journal08.magtechjournal.com/Jwk_wjyx/CN/Y2024/V35/I4/312

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