STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3
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 multi...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-06-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231719303611 |
| _version_ | 1818991267247292416 |
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| author | Ning Li Heng Zhou Haiming Wu Qingqing Wu Mingxia Duan Wei Deng Qizhu Tang |
| author_facet | Ning Li Heng Zhou Haiming Wu Qingqing Wu Mingxia Duan Wei Deng Qizhu Tang |
| author_sort | Ning Li |
| collection | DOAJ |
| 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. Keywords: STING-IRF3, NLRP3 inflammasome, Pyroptosis, Apoptosis, Sepsis-induced cardiomyopathy |
| first_indexed | 2024-12-20T20:07:33Z |
| format | Article |
| id | doaj.art-5067965a743649f49796feebee9f63f5 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-20T20:07:33Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-5067965a743649f49796feebee9f63f52022-12-21T19:27:54ZengElsevierRedox Biology2213-23172019-06-0124STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3Ning Li0Heng Zhou1Haiming Wu2Qingqing Wu3Mingxia Duan4Wei Deng5Qizhu Tang6Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaCorresponding author.; Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaCorresponding author.; Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR ChinaMountainous 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. Keywords: STING-IRF3, NLRP3 inflammasome, Pyroptosis, Apoptosis, Sepsis-induced cardiomyopathyhttp://www.sciencedirect.com/science/article/pii/S2213231719303611 |
| spellingShingle | Ning Li Heng Zhou Haiming Wu Qingqing Wu Mingxia Duan Wei Deng Qizhu Tang STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 Redox Biology |
| title | STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 |
| title_full | STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 |
| title_fullStr | STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 |
| title_full_unstemmed | STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 |
| title_short | STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 |
| title_sort | sting irf3 contributes to lipopolysaccharide induced cardiac dysfunction inflammation apoptosis and pyroptosis by activating nlrp3 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231719303611 |
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