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

Redox biology, 2019-06, Vol.24, p.101215, Article 101215 [Peer Reviewed Journal]

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. ;2019 The Authors 2019 ;ISSN: 2213-2317 ;EISSN: 2213-2317 ;DOI: 10.1016/j.redox.2019.101215 ;PMID: 31121492

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Title:
STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3
Author: Li, Ning ; Zhou, Heng ; Wu, Haiming ; Wu, Qingqing ; Duan, Mingxia ; Deng, Wei ; Tang, Qizhu
Subjects: Animals ; Apoptosis ; Cytokines - blood ; Cytokines - metabolism ; Disease Models, Animal ; Echocardiography ; Heart Diseases - diagnosis ; Heart Diseases - etiology ; Heart Diseases - metabolism ; Heart Diseases - physiopathology ; Interferon Regulatory Factor-3 - genetics ; Interferon Regulatory Factor-3 - metabolism ; Intracellular Space ; Lipopolysaccharides - adverse effects ; Male ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Myocytes, Cardiac - metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; Pyroptosis ; Reactive Oxygen Species ; Research Paper
Is Part Of: Redox biology, 2019-06, Vol.24, p.101215, Article 101215
Description: 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.
Publisher: Netherlands: Elsevier
Language: English
Identifier: ISSN: 2213-2317
EISSN: 2213-2317
DOI: 10.1016/j.redox.2019.101215
PMID: 31121492
Source: MEDLINE
PubMed Central
DOAJ Directory of Open Access Journals

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

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. ;2019 The Authors 2019 ;ISSN: 2213-2317 ;EISSN: 2213-2317 ;DOI: 10.1016/j.redox.2019.101215 ;PMID: 31121492

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