High glucose mediates NLRP3 inflammasome activation via upregulation of ELF3 expression

Jing Wang,Changhong Miao,Weifei Wu,Wankun Chen,Fengfeng Wu,Xuefang Shen,Jing Liu,Zhipeng Meng,Minmin Zhu

doi:10.1038/s41419-020-2598-6

Abstract

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)-1β 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-1β, IL-18, NLRP3 inflammasome and MARK4 expression was increased in diabetic patients and rats. An in vitro study indicated that high glucose increased IL-1β 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.

Highlights

Macrovascular and microvascular disorders have been recognized as important complications in diabetic patients[1]
Previous studies have shown that Microtubule affinity regulating kinase 4 (MARK4) participates in NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activation, mediating IL-1β and IL-18 expression[7,8], so we detected NLRP3 inflammasome and MARK4 expression in diabetic patients
The results showed that siMARK4 decreased high glucose-induced NLRP3 inflammasome activation (Fig. 2f, g) and inhibited high glucose-induced IL-1β and IL-18 mRNA expression in hyperglycaemic human umbilical vein endothelial cells (HUVECs) (Fig. 2h)

Summary

Introduction

Macrovascular and microvascular disorders have been recognized as important complications in diabetic patients[1]. Activation of the NOD-like receptor pyrin domain 3 (NLRP3) inflammasome leads to the generation of bioactive interleukin (IL)-1β and IL-184,5, participating in endothelial inflammation and cardiovascular complications[6]. The NLRP3 inflammasome consists of three parts: NLRP3, caspase-1, and apoptosis-associated speck-like protein (ASC). Microtubule affinity regulating kinase 4 (MARK4) has been reported to play a crucial role in the regulation of NLRP3 inflammasome activation[7,8] and may be a potential target for hyperglycaemiamediated NLRP3 inflammasome activation and endothelial inflammation. In response to inflammatory stimuli, ELF3 expression has been found to be increased in vascular endothelial cells[10]. We hypothesized that ELF3 may increase MARK4 expression, playing a crucial role in hyperglycaemia-induced NLRP3 inflammasome activation in vascular endothelial cells. We explored the potential mechanism by which ELF3 modulates MARK4 expression

Methods

Results

Conclusion