Crucial Role of NLRP3 Inflammasome in the Development of Peritoneal Dialysis-related Peritoneal Fibrosis

Erika Hishida,Tadayoshi Karasawa,Takanori Komada,Hiroaki Kimura,Tetsu Akimoto,Ryo Kamata,Masafumi Takahashi,Sachiko Watanabe,Emi Aizawa,Yoshiyuki Morishita,Daisuke Nagata,Tadashi Kasahara,Homare Ito

doi:10.1038/s41598-019-46504-1

Erika Hishida, Tadayoshi Karasawa + Show 11 more

Open Access

https://doi.org/10.1038/s41598-019-46504-1

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Abstract

Long-term peritoneal dialysis (PD) therapy leads to peritoneal inflammation and fibrosis. However, the mechanism underlying PD-related peritoneal inflammation and fibrosis remains unclear. NLRP3 inflammasome regulates the caspase-1-dependent release of interleukin-1β and mediates inflammation in various diseases. Here, we investigated the role of NLRP3 inflammasome in a murine model of PD-related peritoneal fibrosis induced by methylglyoxal (MGO). Inflammasome-related proteins were upregulated in the peritoneum of MGO-treated mice. MGO induced parietal and visceral peritoneal fibrosis in wild-type mice, which was significantly reduced in mice deficient in NLRP3, ASC, and interleukin-1β (IL-1β). ASC deficiency reduced the expression of inflammatory cytokines and fibrotic factors, and the infiltration of macrophages. However, myeloid cell-specific ASC deficiency failed to inhibit MGO-induced peritoneal fibrosis. MGO caused hemorrhagic ascites, fibrin deposition, and plasminogen activator inhibitor-1 upregulation, but all of these manifestations were inhibited by ASC deficiency. Furthermore, in vitro experiments showed that MGO induced cell death via the generation of reactive oxygen species in vascular endothelial cells, which was inhibited by ASC deficiency. Our results showed that endothelial NLRP3 inflammasome contributes to PD-related peritoneal inflammation and fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder.

Highlights

Accumulating body of evidence suggests that inflammation in the absence of pathogens is mediated via the inflammasome; an intracellular multi-protein complex that regulates release of www.nature.com/scientificreports/
In vitro experiments showed that MGO generated reactive oxygen species (ROS) and induced cell death in endothelial cells, which was inhibited by a caspase recruitment domain (ASC) deficiency
We assessed the expression of inflammasome-related proteins by using real-time RT-PCR analysis and found that the peritoneal expression of NLRP3, ASC, caspase-1, and IL-1β was elevated in a time-dependent manner, and this increase was statistically significant at 21 days after MGO treatment (Fig. 1c)

Summary

Introduction

Accumulating body of evidence suggests that inflammation in the absence of pathogens (sterile inflammation) is mediated via the inflammasome; an intracellular multi-protein complex that regulates release of www.nature.com/scientificreports/. Since caspase-1 is an IL-1β-converting enzyme[12], NLRP3 inflammasome-driven caspase-1 activation induces the processing of pro-IL-1β into its mature form, and the release of this potent inflammatory cytokine IL-1β causes tissue inflammation and damage. Our group recently demonstrated that NLRP3 inflammasome is involved in sterile inflammatory responses in cardiovascular and renal diseases[13,14,15,16,17]. We clearly showed that deficiency of NLRP3, ASC, or IL-1β reduced inflammatory and fibrotic responses in a MGO-induced peritoneal fibrosis model. The present findings showed that endothelial NLRP3 inflammasome contributes to peritoneal inflammatory and fibrotic responses in the pathophysiology of PD-related peritoneal fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder

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