Thioredoxin-1 regulates IRE1α to ameliorate sepsis-induced NLRP3 inflammasome activation and oxidative stress in Raw 264.7 cell

Abstract

Objective: Sepsis is life-threatening organ dysfunction caused by the dysregulated host response to infection. Endoplasmic reticulum stress (ERS)-mediated inositol-requiring enzyme 1 α (IRE1α) inflammatory signaling pathway is involved in sepsis. NLRP3 inflammasome plays a key role in the activation of caspase-1 and the maturation of IL-1β and IL-18, and finally enhances the inflammatory response. More and more evidences show that ERS is an endogenous trigger of NLRP3 inflammasome. Thioredoxin-1 (Trx-1) is a small ubiquitous thiol-1 protein with redox/inflammation modulatory properties relevant to sepsis pathogenesis. In this study, we investigated the role of Trx-1 in ERS mediated IRE1α/NLRP3 signaling pathway in Raw 264.7 cells.

Methods: Raw 264.7 cells stimulated by LPS were used to construct an inflammation model of sepsis in vitro, and the expression of proteins related to the IRE1α/NLRP3 pathway was detected through using western blot and RT-PCR. The expression of IL-18 and IL-1β in cell supernatant was also measured by ELISA, and caspase 1 activity and ROS expression in cells were detected by kits.

Results: Our study shows that IRE1α signaling pathway related to endoplasmic reticulum stress in sepsis can activate inflammation related genes, and stimulate to produce a large number of pro-IL-1β. At the same time, IRE1α can activate NLRP3 inflammasome and promote activation and maturation of pro-IL-1β. Finally leads to excessive inflammatory response and ROS release, and promotes the progress of sepsis.

Conclusions: Trx-1 may inhibit NLRP3 activity and pro-IL-Iβ production by inhibit IRE1α pathway of ER stress. So as to inhibit inflammatory response and ROS of cells, and play a protective role in sepsis.

Keywords:

• Sepsis
• endoplasmic reticulum stress
• IRE1α
• NLRP3
• thioredoxin-1

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

Data that support the study findings are available from the corresponding author upon reasonable request.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was supported by Yunnan Key Laboratory of Innovative Application of Traditional Chinese Medicine (202105AG070032), Yunnan Clinical Medical Center Open Project (2021LCZXXF-HX03), and National Natural Science Foundation of China (No. 81960068, No. 82160366).