Micheliolide Attenuates Lipopolysaccharide-Induced Inflammation by Modulating the mROS/NF-κB/NLRP3 Axis in Renal Tubular Epithelial Cells.

Xianghong Lei,Congwei Luo,Zhaozhong Xu,Yanxia Liu,Yihua Chen,Shuting Li,Fenfen Peng,Qianyin Huang,Haibo Long,Fangqin Zou,Yuxian Wang

doi:10.1155/2020/3934769

Abstract

Chronic kidney disease is a common disease closely related to renal tubular inflammation and oxidative stress, and no effective treatment is available. Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important factor in renal inflammation, but the mechanism remains unclear. Micheliolide (MCL), which is derived from parthenolide, is a new compound with antioxidative and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases. In this study, we investigated the effect of MCL on lipopolysaccharide- (LPS-) induced inflammation in renal tubular cells and the related mechanism. We found that MCL significantly suppressed the LPS-induced NF-κB signaling and inflammatory expression of cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in a rat renal proximal tubular cell line (NRK-52E). MCL also prevented LPS- and adenosine triphosphate-induced NLRP3 inflammasome activation in vitro, as evidenced by the inhibition of NLRP3 expression, caspase-1 cleavage, and interleukin-1β and interleukin-18 maturation and secretion. Additionally, MCL inhibited the reduction of mitochondrial membrane potential and decreases the release of reactive oxygen species (ROS). Moreover, MCL can prevent NLRP3 inflammasome activation induced by rotenone, a well-known mitochondrial ROS (mROS) agonist, indicating that the mechanism of MCL's anti-inflammatory effect may be closely related to the mROS. In conclusion, our study indicates that MCL can inhibit LPS-induced renal inflammation through suppressing the mROS/NF-κB/NLRP3 axis in tubular epithelial cells.

Highlights

Tubular inflammation plays a central role in the loss of renal function in chronic kidney disease (CKD) [1, 2]
We found that rotenone induced nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation, whereas MCL or MitoQ inhibited rotenone-induced NLRP3 inflammasome activation (Figures 5(h)–5(l)), suggesting that MCL inhibits the activation of the NLRP3 inflammasome by reducing the release of mitochondrial ROS (mROS)
In this study, our data showed that MCL can inhibit the activation of the NF-κB pathway and NLRP3 inflammasome by inhibiting the release of mROS, thereby ameliorating tubular inflammation

Summary

Introduction

Tubular inflammation plays a central role in the loss of renal function in chronic kidney disease (CKD) [1, 2]. Renal tubules are the main component of the kidney and are vulnerable to various injuries, such as hypoxia, proteinuria, toxins, metabolic disorders, and aging [2]. Proinflammatory cytokines such as interleukin- (IL-) 1β, IL-18, tumor necrosis factor-α (TNF-α), and chemokines, including monocyte chemoattractant protein-1 (MCP-1), and reactive oxygen species (ROS) are involved in the occurrence and progression of tubular inflammation [2,3,4]. Mounting evidence shows that the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome promotes renal inflammation and contributes to CKD [5].

Methods

Discussion

Conclusion