LncRNA MEG3 promotes pyroptosis via miR-145-5p/TLR4/NLRP3 axis and aggravates cerebral ischemia-reperfusion injury.

IF 3.5 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Lei Li, Hao Zha, Wei Miao, Chunyan Li, Aimei Wang, Shiyuan Qin, Shuang Gao, Lingli Sheng, Ying Wang
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Abstract

Long noncoding RNA (lncRNA) MEG3 has been considered as a novel target for alleviating the brain tissue damage during cerebral ischemia-reperfusion injury (CIRI). Numerous studies have reported that pyroptosis is involved in the pathogenesis of CIRI. This study focused on whether MEG3 modulates CIRI via pyroptosis and its underlying mechanism. The middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model and the oxygen glucose deprivation/reoxygenation (OGD/R) cell model were established. si-MEG3 and miR-145-5p inhibitor were transfected to inhibit MEG3 and miR-145-5p, respectively. As a TLR4 inhibitor, Resatorvid inhibits the TLR4 signaling pathway. TTC and TUNEL staining were used for infarction volume and cell death detection. The differential expression of MGE3, miR-145-5p, TLR4, NLRP3, Caspase-1, IL-1β, and IL-18 was determined using real-time PCR and western blot. The interaction between MEG3 and miR-145-5p, as well as between miR-145-5p and TLR4 was confirmed by the dual-luciferase reporter assay. This study confirmed that the elevated expression of MEG3 during CIRI, and it contributes to pyroptosis by regulating miR-145-5p/TLR4 axis. The knockdown of MEG3 reduced the expression of TLR4, NLRP3, Caspase-1, IL-1β, and IL-18, thereby preventing pyroptosis. Inhibition of miR-145-5p reversed the effect of MEG3 knockdown and promoted pyroptosis. Resatorvid, the inhibitor of TLR4, counteracted the effect of miR-145-5p inhibitor and suppressed pyroptosis. Our findings reveal that MEG3 promotes pyroptosis via miR-145-5p/TLR4/NLRP3 axis and aggravates CIRI, suggesting a potential therapeutic target for ischemic stroke.

LncRNA MEG3通过miR-145-5p/TLR4/NLRP3轴促进焦亡,加重脑缺血再灌注损伤。
长链非编码RNA (lncRNA) MEG3被认为是缓解脑缺血再灌注损伤(CIRI)过程中脑组织损伤的新靶点。大量研究报道焦亡参与CIRI的发病机制。本研究的重点是MEG3是否通过焦亡调节CIRI及其潜在机制。建立小鼠大脑中动脉闭塞/再灌注(MCAO/R)模型和氧糖剥夺/再氧合(OGD/R)细胞模型。转染si-MEG3和miR-145-5p inhibitor,分别抑制MEG3和miR-145-5p。作为TLR4抑制剂,Resatorvid可抑制TLR4信号通路。TTC和TUNEL染色检测梗死体积和细胞死亡。采用real-time PCR和western blot检测MGE3、miR-145-5p、TLR4、NLRP3、Caspase-1、IL-1β和IL-18的差异表达。MEG3与miR-145-5p之间以及miR-145-5p与TLR4之间的相互作用通过双荧光素酶报告基因实验得到证实。本研究证实,在CIRI过程中,MEG3表达升高,并通过调控miR-145-5p/TLR4轴参与焦亡。MEG3的敲除降低了TLR4、NLRP3、Caspase-1、IL-1β和IL-18的表达,从而防止了焦亡。抑制miR-145-5p逆转了MEG3敲低的作用,促进了焦亡。TLR4抑制剂Resatorvid可抵消miR-145-5p抑制剂的作用,抑制焦亡。我们的研究结果表明,MEG3通过miR-145-5p/TLR4/NLRP3轴促进焦亡并加重CIRI,提示其可能是缺血性卒中的治疗靶点。
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来源期刊
Metabolic brain disease
Metabolic brain disease 医学-内分泌学与代谢
CiteScore
5.90
自引率
5.60%
发文量
248
审稿时长
6-12 weeks
期刊介绍: Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.
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