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阿托伐他汀通过 TLR4 和 MyD88 依赖途径抑制脑出血中的 NLRP3 炎性小体激活。

Atorvastatin suppresses NLRP3 inflammasome activation in intracerebral hemorrhage via TLR4- and MyD88-dependent pathways.

机构信息

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.

Department of Pathophysiology, Shenyang Medical College, Shenyang 110034, PR China.

出版信息

Aging (Albany NY). 2022 Jan 11;14(1):462-476. doi: 10.18632/aging.203824.


DOI:10.18632/aging.203824
PMID:35017318
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8791214/
Abstract

Intracerebral hemorrhage (ICH) is a common neurological condition that causes severe disability and even death. Even though the mechanism is not clear, increasing evidence shows the efficacy of atorvastatin on treating ICH. In this study, we examined the impact of atorvastatin on the NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory pathways following ICH. Mouse models of ICH were established by collagenase injection in adult C57BL/6 mice. IHC mice received atorvastatin treatment 2 h after hematoma establishment. First, the changes of glial cells and neurons in the brains of ICH patients and mice were detected by immunohistochemistry and western blotting. Second, the molecular mechanisms underlying the microglial activation and neuronal loss were evaluated after the application of atorvastatin. Finally, the behavioral deficits of ICH mice without or with the treatment of atorvastatin were determined by neurological defect scores. The results demonstrated that atorvastatin significantly deactivated glial cells by reducing the expression of glial fibrillary acidic protein (GFAP), Ionized calcium binding adapter molecule 1 (Iba1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in ICH model mice. For inflammasomes, atorvastatin also showed its efficacy by decreasing the expression of NLRP3, cleaved caspase-1, and IL-1β in ICH mice. Moreover, atorvastatin markedly inhibited the upregulation of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88), which indicated deactivation of NLRP3 inflammasomes. By inhibiting the activities of inflammasomes in glial cells, neuronal loss was partially prevented by suppressing the apoptosis in the brains of ICH mice, protecting them from neurological defects.

摘要

脑出血(ICH)是一种常见的神经系统疾病,可导致严重残疾甚至死亡。尽管其机制尚不清楚,但越来越多的证据表明阿托伐他汀对治疗 ICH 有效。在这项研究中,我们研究了阿托伐他汀对 ICH 后 NOD 样受体蛋白 3(NLRP3)炎性小体和炎症途径的影响。通过在成年 C57BL/6 小鼠中注射胶原酶建立 ICH 小鼠模型。ICH 小鼠在血肿形成后 2 小时接受阿托伐他汀治疗。首先,通过免疫组织化学和蛋白质印迹法检测 ICH 患者和小鼠大脑中神经胶质细胞和神经元的变化。其次,评估了应用阿托伐他汀后小胶质细胞激活和神经元丢失的分子机制。最后,通过神经缺陷评分确定了有无阿托伐他汀治疗的 ICH 小鼠的行为缺陷。结果表明,阿托伐他汀通过降低 ICH 模型小鼠中神经胶质纤维酸性蛋白(GFAP)、离子钙结合接头分子 1(Iba1)、肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6 的表达,显著抑制神经胶质细胞的激活。对于炎性小体,阿托伐他汀通过降低 ICH 小鼠中 NLRP3、切割的半胱天冬酶-1 和 IL-1β的表达,也显示出其疗效。此外,阿托伐他汀还显著抑制了 Toll 样受体 4(TLR4)和髓样分化因子 88(MyD88)的上调,这表明 NLRP3 炎性小体的失活。通过抑制神经胶质细胞中的炎性小体的活性,抑制 ICH 小鼠大脑中的细胞凋亡,部分阻止了神经元的丢失,从而保护其免受神经缺陷的影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/fc3f5b1876fa/aging-14-203824-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/cf4996ecb7d6/aging-14-203824-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/80546b825c07/aging-14-203824-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/dfa69dd79f08/aging-14-203824-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/6660bcc2e5f1/aging-14-203824-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/5355ed1fce6a/aging-14-203824-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/881a93d2b67d/aging-14-203824-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/fc3f5b1876fa/aging-14-203824-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/cf4996ecb7d6/aging-14-203824-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/80546b825c07/aging-14-203824-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/dfa69dd79f08/aging-14-203824-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/6660bcc2e5f1/aging-14-203824-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/5355ed1fce6a/aging-14-203824-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/881a93d2b67d/aging-14-203824-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/792c/8791214/fc3f5b1876fa/aging-14-203824-g007.jpg

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本文引用的文献

[1]
IGF-1R stimulation alters microglial polarization via TLR4/NF-κB pathway after cerebral hemorrhage in mice.

Brain Res Bull. 2020-11

[2]
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J Stroke. 2020-1

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Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage.

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