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氧化三甲胺通过FTO/IGF2BP2促进小胶质细胞的NLRP3炎性小体激活，加重缺血性脑卒中的神经损伤。

TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2.

作者信息

Ge Pengxin, Duan Huijie, Tao Chunrong, Niu Sensen, Hu Yiran, Duan Rui, Shen Aizong, Sun Yancai, Sun Wen

机构信息

Department of Pharmacy, Anhui Provincial Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, People's Republic of China.

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.

出版信息

J Inflamm Res. 2023 Aug 28;16:3699-3714. doi: 10.2147/JIR.S399480. eCollection 2023.

DOI:10.2147/JIR.S399480
PMID:37663757
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10473438/
Abstract

OBJECTIVE

Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear.

MATERIALS AND METHODS

Mice were fed with 0.12% TMAO for 16 weeks. Then, mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in ischemic stroke, microglia of MCAO/R mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia.

RESULTS

TMAO promoted the release of inflammatory cytokines in the brain of MCAO/R mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating ischemic stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3. TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2.

CONCLUSION

Our results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. These findings explained the molecular mechanism of TMAO aggravating ischemic stroke in detail and provided molecular mechanism for clinical treatment.

摘要

目的

中风是一种死亡率很高的脑血管疾病。已表明氧化三甲胺（TMAO）会加重中风后果，但其机制仍不清楚。

材料与方法

给小鼠喂食0.12%的TMAO，持续16周。然后，将小鼠制成大脑中动脉闭塞/再灌注（MCAO/R）模型。评估神经学评分、梗死体积、神经元损伤以及与炎症相关的标志物。由于小胶质细胞在缺血性中风中起关键作用，分离MCAO/R小鼠的小胶质细胞进行高通量测序，以鉴定TMAO处理后差异表达最明显的基因。随后，使用原代小胶质细胞研究TMAO的下游通路。

结果

TMAO促进了MCAO/R小鼠脑中炎性细胞因子的释放，并促进氧糖剥夺/再灌注（OGD/R）小胶质细胞炎性小体的激活，从而加重缺血性中风后果。FTO/IGF2BP2通过下调NLRP3的m6A水平抑制OGD/R小胶质细胞中NLRP3炎性小体的激活。TMAO可抑制FTO和IGF2BP2的表达，从而促进OGD/R小胶质细胞中NLRP3炎性小体的激活。总之，这些结果表明，TMAO通过FTO/IGF2BP2促进小胶质细胞NLRP3炎性小体的激活，加重缺血性中风中的神经损伤。

结论

我们的结果表明，TMAO通过FTO/IGF2BP2促进小胶质细胞NLRP3炎性小体的激活，加重缺血性中风中的神经损伤。这些发现详细解释了TMAO加重缺血性中风的分子机制，并为临床治疗提供了分子机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/e45e239d8ac4/JIR-16-3699-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/f0c9424aedf5/JIR-16-3699-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/f8a188f52e0f/JIR-16-3699-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/41017744f0b4/JIR-16-3699-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/de7416cd06fa/JIR-16-3699-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/41afa3c24a8e/JIR-16-3699-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/e155364df2b0/JIR-16-3699-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/e45e239d8ac4/JIR-16-3699-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/f0c9424aedf5/JIR-16-3699-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/f8a188f52e0f/JIR-16-3699-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/41017744f0b4/JIR-16-3699-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/de7416cd06fa/JIR-16-3699-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/41afa3c24a8e/JIR-16-3699-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/e155364df2b0/JIR-16-3699-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d7a/10473438/e45e239d8ac4/JIR-16-3699-g0007.jpg

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