NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice.
NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice.
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NOD1/RIP2信号增强小胶质细胞驱动的炎症反应，并与炎症细胞因子相互作用，加剧小鼠脑出血后的脑损伤
DOI：
10.1186/s12974-020-02015-9
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发表时间：
2020-12-01
影响因子：
9.3
通讯作者：
Cui G
中科院分区：
文献类型：
--
作者：
Wang M;Ye X;Hu J;Zhao Q;Lv B;Ma W;Wang W;Yin H;Hao Q;Zhou C;Zhang T;Wu W;Wang Y;Zhou M;Zhang CH;Cui G
研究背景先天性免疫反应和随后的促炎因子产生所引起的继发性脑损伤是导致脑出血（intracerebral hemorrhage，ICH）高死亡率的主要因素。核苷酸结合寡聚化结构域1（NOD 1）/受体相互作用蛋白2（RIP 2）信号转导已被报道参与先天免疫应答和炎症应答。因此，我们研究了NOD 1/RIP 2信号转导在胶原酶诱导的ICH小鼠和培养的原代小胶质细胞中的作用，用hemin.MethodsAdult雄性C57 BL/6小鼠进行胶原酶诱导ICH模型在体内。培养的原代小胶质细胞和BV 2小胶质细胞（小胶质细胞系）用氯化血红素攻击，旨在模拟体外ICH模型。我们首先定义了NOD 1和RIP 2的表达在体内和体外使用ICH模型通过蛋白质印迹。脑室内注射ML 130（NOD 1抑制剂）或GSK 583（RIP 2抑制剂）后，评估NOD 1/RIP 2信号传导对ICH诱导的脑损伤体积、神经功能缺损、脑水肿和小胶质细胞活化的影响。此外，在ICH激发的脑和氯化血红素暴露的培养的原代小胶质细胞中，通过蛋白质印迹法分析JNK/P38 MAPK、IκBα和炎性因子（包括肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β和诱导型一氧化氮合酶（iNOS）表达）的水平。结果脑出血小鼠脑组织中NOD 1及其衔接子RIP 2的表达水平明显升高，在培养的原代小胶质细胞和经氯化血红素刺激的BV 2细胞中NOD 1及其衔接子RIP 2的表达水平也明显升高。在患有ICH的小鼠中施用NOD 1或RIP 2抑制剂可防止小胶质细胞活化和神经炎症，随后减轻ICH诱导的脑损伤。结论NOD 1/RIP 2信号通路在脑出血时的炎症反应中起重要作用。此外，NOD 1/RIP 2与IL-1β/TNF-α之间存在恶性反馈循环，可能在一定程度上导致脑出血时持续性脑损伤。因此，我们的研究强调NOD 1/RIP 2信号传导作为一个潜在的治疗靶点，以保护脑免受继发性脑损伤在ICH。
BackgroundSecondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral haemorrhage (ICH). Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response. Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin.MethodsAdult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo. Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro. We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting. The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor). In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting. Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2.ResultsThe levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin. Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage. Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study.ConclusionNOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH. In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH. Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.
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影响因子：
11.2
作者：
Karuppagounder SS;Alin L;Chen Y;Brand D;Bourassa MW;Dietrich K;Wilkinson CM;Nadeau CA;Kumar A;Perry S;Pinto JT;Darley-Usmar V;Sanchez S;Milne GL;Pratico D;Holman TR;Carmichael ST;Coppola G;Colbourne F;Ratan RR
通讯作者：
Ratan RR
影响因子：
8.3
作者：
He Y;Xu L;Li B;Guo ZN;Hu Q;Guo Z;Tang J;Chen Y;Zhang Y;Tang J;Zhang JH
通讯作者：
Zhang JH
影响因子：
9.3
作者：
Bhatia HS;Baron J;Hagl S;Eckert GP;Fiebich BL
通讯作者：
Fiebich BL
DOI：
10.1016/j.bbi.2016.12.012
发表时间：
2017-03
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Lan X;Han X;Li Q;Li Q;Gao Y;Cheng T;Wan J;Zhu W;Wang J
通讯作者：
Wang J
影响因子：
3.1
作者：
Biondo, C.;Mancuso, G.;Beninati, C.
通讯作者：
Beninati, C.