TGR5 activation attenuates neuroinflammation via Pellino3 inhibition of caspase-8/NLRP3 after middle cerebral artery occlusion in rats.
TGR5 activation attenuates neuroinflammation via Pellino3 inhibition of caspase-8/NLRP3 after middle cerebral artery occlusion in rats.
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TGR5激活通过大鼠中大脑中动脉闭塞后的caspase-8/nlrp3抑制pellino3抑制神经炎症。
DOI：
10.1186/s12974-021-02087-1
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发表时间：
2021-02-02
影响因子：
9.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Liang H;Matei N;McBride DW;Xu Y;Zhou Z;Tang J;Luo B;Zhang JH
核苷酸结合寡聚化结构域样受体pyrin结构域含蛋白3 （NLRP3）在缺血性脑卒中中介导炎症反应中起重要作用。胆汁酸受体Takeda-G-protein-receptor-5 （TGR5）已被确定为调节脑炎症反应的重要组成部分。在这项研究中，我们探讨了TGR5在缓解大脑中动脉闭塞（MCAO）后神经炎症的机制。Sprague-Dawley大鼠进行MCAO， MCAO后1小时鼻内给予TGR5激动剂INT777。在MCAO前48 h通过脑室内注射靶向TGR5和Pellino3的小干扰rna （siRNA）。评估梗死体积和神经学评分，采用ELISA、流式细胞术、免疫荧光染色、免疫印迹和免疫共沉淀法进行评估。MCAO后内源性TGR5和Pellino3水平升高。通过INT777激活TGR5可显著降低促炎细胞因子、裂解型caspase-8和NLRP3水平，从而减少脑梗死；短期和长期的神经行为评估都显示出改善。缺血损伤诱导TGR5与Pellino3相互作用。TGR5或Pellino3的下调增加了cleaved caspase-8和NLRP3的积累，加重了脑损伤，并消除了MCAO后INT777的抗炎作用。TGR5激活通过抑制MCAO后的神经炎症减轻脑损伤，这可能是由Pellino3抑制caspase-8/NLRP3介导的。在线版本包含补充材料，可在10.1186/s12974-021-02087-1获得。
Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke. Bile acid receptor Takeda-G-protein-receptor-5 (TGR5) has been identified as an important component in regulating brain inflammatory responses. In this study, we investigated the mechanism of TGR5 in alleviating neuroinflammation after middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were subjected to MCAO and TGR5 agonist INT777 was administered intranasally 1 h after MCAO. Small interfering RNAs (siRNA) targeting TGR5 and Pellino3 were administered through intracerebroventricular injection 48 h before MCAO. Infarct volumes and neurologic scores were evaluated, and ELISA, flow cytometry, immunofluorescence staining, immunoblotting, and co-immunoprecipitation were used for the evaluations. Endogenous TGR5 and Pellino3 levels increased after MCAO. TGR5 activation by INT777 significantly decreased pro-inflammatory cytokine, cleaved caspase-8, and NLRP3 levels, thereby reducing brain infarctions; both short- and long-term neurobehavioral assessments showed improvements. Ischemic damage induced the interaction of TGR5 with Pellino3. Knockdown of either TGR5 or Pellino3 increased the accumulation of cleaved caspase-8 and NLRP3, aggravated cerebral impairments, and abolished the anti-inflammatory effects of INT777 after MCAO. TGR5 activation attenuated brain injury by inhibiting neuroinflammation after MCAO, which could be mediated by Pellino3 inhibition of caspase-8/NLRP3. The online version contains supplementary material available at 10.1186/s12974-021-02087-1.
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