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

May 24, 2019Redox biology

STING-IRF3 may cause heart problems, inflammation, and cell death after bacterial toxin by activating NLRP3

AI simplified

Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

Knockout of STING in mice significantly improved survival rate and cardiac function.

Inflammation, cardiomyocyte cell death, and a specific type of cell death called pyroptosis are linked to sepsis and its effects on the heart.
In response to a bacterial component (LPS), STING moves to specific areas in the cell, interacts with proteins that regulate immune responses, and promotes inflammation.
Mice lacking STING exhibited reduced levels of inflammatory substances and less heart damage compared to normal mice when exposed to LPS.
In laboratory tests, increasing levels of a protein called NLRP3 counteracted the protective effects observed when STING was reduced.
Exposure to LPS also led to increased production of reactive oxygen species, which contributed to the harmful movement of NLRP3 within the cell.

AI simplified

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.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (XML) ↗View full text ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week: