Ethyl Pyruvate Attenuates Microglial NLRP3 Inflammasome Activation via Inhibition of HMGB1/NF-κB/miR-223 Signaling.

Melis Olcum,Irem Nur Gokbayrak,Kemal Ugur Tufekci,Devrim Yagmur Durur,Bora Tastan,Sermin Genc,Kursad Genc

doi:10.3390/antiox10050745

Melis Olcum, Irem Nur Gokbayrak + Show 5 more

Open Access

https://doi.org/10.3390/antiox10050745

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Journal: Antioxidants	Publication Date: May 8, 2021
Citations: 11	License type: CC BY 4.0

Affiliation: Izmir University, Dokuz Eylül University

Abstract

Ethyl pyruvate is a molecule with anti-inflammatory and pro-metabolic effects. Ethyl pyruvate has been shown to ameliorate the clinical and pathological findings of neurodegenerative diseases such as Alzheimer’s and Parkinson’s Diseases in rodents. Its anti-inflammatory and neuroprotective effects are widely investigated in animal and cellular models. Our study aimed to investigate the mechanism of the impact of Ethyl pyruvate on NLRP3 inflammasome activation in the N9 microglial cell line. Our results indicated that ethyl pyruvate significantly suppressed LPS and ATP-induced NLRP3 inflammasome activation, decreased active caspase-1 level, secretion of IL-1β and IL-18 cytokines, and reduced the level of pyroptotic cell death resulting from inflammasome activation. Furthermore, ethyl pyruvate reduced the formation of total and mitochondrial ROS and suppressed inflammasome-induced HMGB1 upregulation and nuclear NF-κB translocation and reversed the inflammasome activation-induced miRNA expression profile for miR-223 in N9 cells. Our study suggests that ethyl pyruvate effectively suppresses the NLRP3 inflammasome activation in microglial cells regulation by miR-223 and NF-κB/HMGB1 axis.

Highlights

Microglial cells are the primary innate immune component of the central nervous system (CNS), which make up 10–15% of the brain [1]
With the 10 mM pre-incubation of ethyl pyruvate (EP), the rate of IL-1β increased with LPS and ATP decreased statistically (p = 0.0079) (Figure 1D)
We examined intracellular level significantly increased in ATP-induced cells, pre-treatmitochondrial ROS production and mitochondrial membrane potential in N9 microglial cells.with

Summary

Introduction

Microglial cells are the primary innate immune component of the central nervous system (CNS), which make up 10–15% of the brain [1]. They are mainly involved in maintaining tissue homeostasis by constantly scavenging the environment for possible threats and initiating the proper inflammatory responses, including inflammasomes. NOD-like receptor (NLR) family of PRRs can recognize damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) to activate the appropriate inflammatory response [5]. NLRP3 inflammasome complex is one of the inflammatory responsive complexes of the NLR family, which is activated via ATP and leads to pro-inflammatory cytokine release and pyroptotic cell death [6]. The proteolytic multiprotein complex structure of the NLRP3 inflammasome complex induces the caspase-1 enzyme to get activated

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