STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3

Ning Li,Heng Zhou,Haiming Wu,Qingqing Wu,Mingxia Duan,Wei Deng,Qizhu Tang

doi:10.1016/j.redox.2019.101215

Ning Li, Heng Zhou + Show 5 more

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https://doi.org/10.1016/j.redox.2019.101215

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Journal: Redox Biology	Publication Date: May 13, 2019
Citations: 342	License type: cc-by

Affiliation: Renmin Hospital of Wuhan University

Abstract

Mountainous evidence suggests that inflammation, cardiomyocyte apoptosis and pyroptosis are involved in the development of sepsis and sepsis-induced cardiomyopathy (SIC). Stimulator of interferon genes (STING) is an indispensable molecule that could regulate inflammation and immune response in multiple diseases. However, the role of STING in cardiovascular disease, especially SIC remains unclear. This study was designed to investigate the potential molecular mechanisms of STING in lipopolysaccharide (LPS)-induced cardiac injury using STING global knockout mice. In wild type mice and cardiomyocytes, LPS stimulation triggered the perinuclear translocation of STING, which further bound to Type-I interferons (IFN) regulatory factor 3 (IRF3) and phosphorylated IRF3. Phosphorylated (P-) IRF3 subsequently translocated into nucleus and increased the expression of NOD-like receptor protein 3 (NLRP3). Knockout of STING in mice significantly improved survival rate and cardiac function, apart from suppressing myocardial and serum inflammatory cytokines, apoptosis, as well as cardiomyocyte pyroptosis. In vitro experiments revealed that NLRP3 overexpression by adenovirus could offset protective effects of STING knockdown in LPS-induced cardiomyocytes. Additionally, LPS stimulation also promoted the production of intracellular reactive oxygen (ROS), which further induced the NLRP3 translocation to the cytoplasm from the nucleus. Dissociative TXNIP could directly interact with cytoplasmic NLRP3 and form inflammasome, eventually triggering cardiomyocyte injury. Collectively, our findings disclose that STING deficiency could alleviate LPS-induced SIC in mice. Hence, targeting STING in cardiomyocytes may be a promising therapeutic strategy for preventing SIC.

Highlights

Sepsis is a lethal syndrome caused by a series of inappropriate immune responses, which has been estimated to cause annual death of 200,000 in America [1]
Our findings demonstrated that Stimulator of interferon genes (STING)-IRF3 could trigger LPS
We provided evidence that LPS-induced ROS generation in cardiomyocytes played an essential role in the export of NOD-like receptor protein 3 (NLRP3) from the nucleus to the cytoplasm, which was independent of the expression of STING (Fig. 10)

Summary

Introduction

Sepsis is a lethal syndrome caused by a series of inappropriate immune responses, which has been estimated to cause annual death of 200,000 in America [1]. Sepsis may develop into systemic inflammatory response syndrome (SIRS) unless it is controlled properly and promptly, eventually giving rise to multiple organ dysfunction (MOD) [2]. The earliest clinical manifestation in patients with SIC is cardiac dysfunction, which has 3 features: dilated left ventricle, declined ejection fraction, as well as recovery in 7–10 days [3]. At the cellular and molecular level, inflammation, apoptosis and pyroptosis are regarded as critical pathophysiology phenomenons in sepsis and SIC [4,5,6].

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