High glucose mediates NLRP3 inflammasome activation via upregulation of ELF3 expression
High glucose mediates NLRP3 inflammasome activation via upregulation of ELF3 expression
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高葡萄糖通过上调 ELF3 表达介导 NLRP3 炎症小体激活
DOI：
10.1038/s41419-020-2598-6
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发表时间：
2020-05-21
影响因子：
9
通讯作者：
Miao, Changhong
中科院分区：
文献类型：
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作者：
Wang, Jing;Shen, Xuefang;Miao, Changhong
微管亲和力调节激酶4（MARK 4）在调节NOD样受体pyrin结构域3（NLRP 3）炎性小体活化中起关键作用，其导致生物活性白细胞介素（IL）-1 β和IL-18的产生。E74样ETS转录因子3（ELF 3）参与内皮炎症过程。我们假设ELF 3调节血管内皮细胞中MARK 4的表达，从而促进高糖介导的NLRP 3炎性小体激活。在糖尿病患者和大鼠中，血浆IL-1 β、IL-18、NLRP 3炎性体和MARK 4表达增加。一项体外研究表明，高糖增加了IL-1 β和IL-18的表达，并通过上调人脐静脉内皮细胞（HUVEC）中的MARK 4激活了NLRP 3炎性体。此外，高糖增加ELF 3表达。ELF 3下调逆转了高糖处理的作用。因此，ELF 3过表达的效果与高糖处理的效果相似，并且被siMARK 4抵消。此外，发现ELF 3与SET 8相互作用。高糖抑制SET 8表达和组蛋白H4赖氨酸20甲基化（H4 K20 me 1），SET 8的下游靶点。SET 8的过表达抑制高糖诱导的MARK 4表达和NLRP 3炎性小体激活。shSET 8的作用与高糖处理的作用相似，并且被siMARK 4抵消。一项机制研究发现，ELF 3和H4 K20 me 1富集在MARK 4启动子区。si-ELF 3减弱了MARK 4启动子活性，增强了SET 8对MARK 4启动子活性的抑制作用。此外，在糖尿病患者和大鼠中证实了SET 8下调和ELF 3上调。总之，ELF 3与SET 8相互作用以调节MARK 4表达，MARK 4参与高血压介导的内皮NLRP 3炎性体激活。
Microtubule affinity regulating kinase 4 (MARK4) plays a crucial role in the regulation of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activation, which leads to the generation of bioactive interleukin (IL)-1 beta and IL-18. E74-like ETS transcription factor 3 (ELF3) participates in endothelial inflammatory processes. We hypothesized that ELF3 modulates MARK4 expression in vascular endothelial cells, thus contributing to high glucose-mediated NLRP3 inflammasome activation. Plasma IL-1 beta, IL-18, NLRP3 inflammasome and MARK4 expression was increased in diabetic patients and rats. An in vitro study indicated that high glucose increased IL-1 beta and IL-18 expression and activated the NLRP3 inflammasome via upregulation of MARK4 in human umbilical vein endothelial cells (HUVECs). Furthermore, high glucose increased ELF3 expression. ELF3 downregulation reversed the effects of high glucose treatment. Accordingly, the effects of ELF3 overexpression were similar to those of high glucose treatment and were counteracted by siMARK4. Furthermore, ELF3 was found to interact with SET8. High glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. Overexpression of SET8 inhibited high glucose-induced MARK4 expression and NLRP3 inflammasome activation. The effects of shSET8 were similar to those of high glucose treatment and were counteracted by siMARK4. A mechanistic study found that ELF3 and H4K20me1 were enriched in the MARK4 promoter region. si-ELF3 attenuated MARK4 promoter activity and augmented the inhibitory effect of SET8 on MARK4 promoter activity. Furthermore, SET8 downregulation and ELF3 upregulation were confirmed in diabetic patients and rats. In conclusion, ELF3 interacted with SET8 to modulate MARK4 expression, which participated in hyperglycaemia-mediated endothelial NLRP3 inflammasome activation.