SLC15A3 is transcriptionally regulated by HIF1α and p65 to worsen neuroinflammation in experimental ischemic stroke.

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-08 DOI:10.1007/s12035-024-04191-8
Shan Yu, Jinghui Yang, Rui Zhang, Qian Guo, Lu Wang
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Abstract

Systemic inflammatory stimulus is a risk factor for the incidence of ischemic stroke and contributes to poorer clinical outcomes. Solute carrier 15A3 (SLC15A3) is a peptide/histidine transporter that is implicated in regulating inflammatory responses. However, whether SLC15A3 affects the progression of ischemic stroke associated with systemic inflammation is unclear. The transient middle cerebral artery occlusion (tMCAO) mice with LPS administration (LPS/tMCAO) were prepared as an in vivo model, and LPS-induced BV2 cells under oxygen-glucose deprivation (OGD) exposure were utilized as an in vitro model. We found that SLC15A3 was highly expressed in the ischemic penumbra of LPS/tMCAO mice, and its inhibition reduced infarct area, attenuated neurological deficit, recovered motor function, and mitigated apoptotic neurons. Knockdown of SLC15A3 suppressed the proinflammatory M1-type markers and promoted the levels of M2-associated genes. The in vitro results confirmed that SLC15A3 overexpression promoted microglia polarizing towards M1 subtypes, while SLC15A3 inhibition exerted an opposite effect. In addition, we demonstrated that the p65 signaling pathway and HIF1α were activated by LPS/OGD. Luciferase reporter assay showed that inhibiting p65 using its specific inhibitor BAY 11-7082 or silencing HIF1α using siRNAs reduced the transcriptional activity of SLC15A3 in LPS/OGD-induced BV2 cells. Results in NIH 3T3 cells also confirmed that p65 and HIF1α directly bound to the SLC15A3 promoter to activate SLC15A3 transcription. In conclusion, this work shows that SLC15A3, transcriptionally activated by p65 and HIF1α, contributes to poor outcomes in ischemic stroke associated with systemic inflammation by promoting microglial cells polarizing towards M1 types.

Abstract Image

SLC15A3 受 HIF1α 和 p65 的转录调控,从而加重实验性缺血性中风的神经炎症。
全身性炎症刺激是缺血性脑卒中发病率的一个危险因素,并导致较差的临床预后。溶质运载体 15A3(SLC15A3)是一种肽/组氨酸转运体,与调节炎症反应有关。然而,SLC15A3 是否会影响与全身炎症相关的缺血性中风的进展尚不清楚。我们制备了一过性大脑中动脉闭塞(tMCAO)并给予 LPS 的小鼠(LPS/tMCAO)作为体内模型,并利用 LPS 诱导的 BV2 细胞在氧-葡萄糖剥夺(OGD)暴露下作为体外模型。我们发现,SLC15A3在LPS/tMCAO小鼠缺血半影中高表达,抑制SLC15A3可缩小梗死面积,减轻神经功能缺损,恢复运动功能,减轻神经元凋亡。敲除 SLC15A3 可抑制促炎的 M1 型标志物,提高 M2 相关基因的水平。体外研究结果证实,SLC15A3过表达会促进小胶质细胞向M1亚型极化,而抑制SLC15A3则会产生相反的效果。此外,我们还证实了 LPS/OGD 激活了 p65 信号通路和 HIF1α。荧光素酶报告实验表明,使用特异性抑制剂 BAY 11-7082 抑制 p65 或使用 siRNAs 沉默 HIF1α 可降低 LPS/OGD 诱导的 BV2 细胞中 SLC15A3 的转录活性。在 NIH 3T3 细胞中的研究结果也证实,p65 和 HIF1α 直接与 SLC15A3 启动子结合,激活了 SLC15A3 的转录。总之,这项工作表明,SLC15A3 在 p65 和 HIF1α 的转录激活下,通过促进小胶质细胞向 M1 型极化,导致与全身炎症相关的缺血性中风的不良预后。
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来源期刊
Molecular Neurobiology
Molecular Neurobiology 医学-神经科学
CiteScore
9.00
自引率
2.00%
发文量
480
审稿时长
1 months
期刊介绍: Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.
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