IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury.
IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury.
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DOI：
10.1186/s12974-023-02934-3
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发表时间：
2023-10-26
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
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作者：
神经炎症导致创伤性脑损伤(TBI)后继发性损伤的级联反应，炎症和消退交替发生。白介素1(IL-1)是一种重要的神经炎性介质，起源于脑内皮细胞、小胶质细胞、星形胶质细胞和外周免疫细胞，在颅脑损伤后急剧过度表达，传播继发性损伤和组织损伤。IL-1影响血脑屏障通透性、免疫细胞活化和神经可塑性。尽管脑外伤后细胞因子信号转导的复杂性，我们假设IL-1信号转导特异性地调节神经炎性反应成分。采用闭合性颅脑损伤模型，采用一种新的IL-1受体(IL-1R1)全局敲除小鼠模型，研究了IL-1‘S在神经炎症级联反应中的作用。我们发现，IL-1R1GKO减轻了损伤后14周的行为损害，并减少了新皮质、胼胝体和海马区反应性小胶质细胞和星形胶质细胞的染色。然后，我们研究了IL-1R1丢失是否改变了急性神经炎性动力学，使用NanoString神经炎性小组测量了CHI后3、9、24和72小时新皮质中基因表达的变化。在分析的757个基因中，IL-1R1信号在神经炎性基因调控中表现出时间特异性，主要影响在CHI后9h。IL-1R1信号特异性地影响星形胶质细胞相关基因，选择性地上调趋化因子，如CCL2、CCL3和CCL4，而对细胞因子调节，如肿瘤坏死因子α的影响有限。这项研究进一步揭示了IL-1R1在放大小鼠CHI后神经炎性级联反应中的作用，并证明抑制IL-1R1信号对大脑健康具有长期保护作用。网上版载有补充材料，可在10.1186/s12974-023-02934-3查阅。
Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood–brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health. The online version contains supplementary material available at 10.1186/s12974-023-02934-3.
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DOI：
10.3791/64556
发表时间：
2022-09-28
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Macheda T;Roberts K;Bachstetter AD
通讯作者：
Bachstetter AD
DOI：
10.1016/j.bbih.2020.100143
发表时间：
2020-12
期刊：
Brain, behavior, & immunity - health
影响因子：
--
作者：
Criado-Marrero M;Smith TM;Gould LA;Kim S;Penny HJ;Sun Z;Gulick D;Dickey CA;Blair LJ
通讯作者：
Blair LJ
影响因子：
7.3
作者：
Bodnar CN;Watson JB;Higgins EK;Quan N;Bachstetter AD
通讯作者：
Bachstetter AD
影响因子：
11
作者：
DiSabato DJ;Nemeth DP;Liu X;Witcher KG;O'Neil SM;Oliver B;Bray CE;Sheridan JF;Godbout JP;Quan N
通讯作者：
Quan N
影响因子：
5.3
作者：
Liu, Xiaoyu;Yamashita, Tetsuji;Quan, Ning
通讯作者：
Quan, Ning