Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

Li, Ning; Wang, Wei; Jiang, Wenyang; Xiong, Rui; Qian, Geng

doi:10.1002/ctm2.228

Cited by 161 publications

(139 citation statements)

References 47 publications

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“… 28 We recently reported that NLRP3 inflammasome-dependent macrophage pyroptosis may also contribute to lung injury caused by sepsis. 6 Hence, inflammasome inhibition may serve as a pharmacological target for relieving ALI induced by infection or trauma. In this study, we reported that NLRP3 inflammasome and pyroptosis could be inhibited by MF in LPS-treated lung tissues and macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…All experimental animal in our study were fed in a specific-pathogen-free (SPF) environment (humidity 50 ± 3%, temperature 22–25◦C). As described previously, 6 to establish the murine ALI model, LPS was dissolved in 50 μL sterile saline and instilled intratracheally at a dose of 5 mg/kg. An isovolumetric sterile saline was instilled intratracheally in mice from the control group.…”

Section: Methodsmentioning

confidence: 99%

“… 5 Our team recently reported that NLRP3 inflammasome activation by mitochondrial DNA is one of the critical mechanisms contributing to sepsis-induced ALI. 6 And pharmacological inhibition or genetic ablation of NLRP3 activation could lead to potent beneficial effects in lung diseases, especially in sepsis-induced ALI. 7 Hence, targeted inhibition of NLRP3 inflammasome activation or its upstream regulation molecules in lung tissues could be a possible strategy for the prevention of ALI.…”

Section: Introductionmentioning

confidence: 99%

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Mangiferin Mitigates Lipopolysaccharide-Induced Lung Injury by Inhibiting NLRP3 Inflammasome Activation

Li¹,

Xiong²,

He³

et al. 2021

JIR

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Scope Mangiferin (MF) is a natural phytopolyphenol, which displays potential pharmacological properties involving antibacterial, anti-inflammation, antioxidant and anti-tumor. However, little is known about the roles of MF in lung injury. The aim of this study is to demonstrate the modulatory effects and molecular mechanisms by which MF operates in sepsis-induced lung injury. Methods and Results To examine the protective properties of MF, an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice and an in vitro model of LPS-treated J774A.1 cells were established, respectively. The results revealed that MF treatment significantly relieved LPS-induced pathological injury and inflammatory response in murine lung tissues. Meanwhile, MF treatment also inhibited nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and pyroptosis induced by LPS. In macrophage-specific NLRP3 deficiency mice treated with LPS, MF showed little protective effects. NLRP3 overexpression by adenovirus could also offset the beneficial effects of MF in LPS-treated J774A.1 cells. Furthermore, we found that MF could suppress the expression of NLPR3 and pyroptosis of macrophages by inhibiting the nuclear translocation of the nuclear factor-κB (NF-κB) subunits P50 and P65. Conclusion MF protects against lung injury and inflammatory response by inhibiting NLRP3 inflammasome activation in a NF-κB-dependent manner in macrophages, which provides a promising therapeutic candidate for the treatment of lung injury.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mangiferin Mitigates Lipopolysaccharide-Induced Lung Injury by Inhibiting NLRP3 Inflammasome Activation

Li¹,

Xiong²,

He³

et al. 2021

JIR

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“…In addition to intracellular cytosolic "self-DNA," exosome secretory and circulatory cell-free mtDNA are also suggested to contribute to AIM2 inflammasome-mediated inflammation [57]. have been shown to be associated in multiple sets, such as acute lung injury [58] and age-related liver ischemiareperfusion injury (IRI) [59]. Typically, the stimulated cGAS-STING axis initiates inflammasome assembly and activation via type-I IFN signaling [60,61] or K+ efflux induced by the translocation of STING to the lysosome and the subsequent lysosomal rupture [62].…”

Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Mitochondrial DNA‐Mediated Inflammation in Acute Kidney Injury and Chronic Kidney Disease

Jin

Armando

et al. 2021

Oxidative Medicine and Cellular Longevity

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The integrity and function of mitochondria are essential for normal kidney physiology. Mitochondrial DNA (mtDNA) has been widely a concern in recent years because its abnormalities may result in disruption of aerobic respiration, cellular dysfunction, and even cell death. Particularly, aberrant mtDNA copy number (mtDNA-CN) is associated with the development of acute kidney injury and chronic kidney disease, and urinary mtDNA-CN shows the potential to be a promising indicator for clinical diagnosis and evaluation of kidney function. Several lines of evidence suggest that mtDNA may also trigger innate immunity, leading to kidney inflammation and fibrosis. In mechanism, mtDNA can be released into the cytoplasm under cell stress and recognized by multiple DNA-sensing mechanisms, including Toll-like receptor 9 (TLR9), cytosolic cGAS-stimulator of interferon genes (STING) signaling, and inflammasome activation, which then mediate downstream inflammatory cascades. In this review, we summarize the characteristics of these mtDNA-sensing pathways mediating inflammatory responses and their role in the pathogenesis of acute kidney injury, nondiabetic chronic kidney disease, and diabetic kidney disease. In addition, we highlight targeting of mtDNA-mediated inflammatory pathways as a novel therapeutic target for these kidney diseases.

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“…Western blot was performed as our previously described 17 . Extracting the total proteins of fresh ventricle tissues or iced cell lysates and quanti ed, approximately 50 µg of total proteins were loaded on an SDS/PAGE gel.…”

Section: Western Blot and Real-time Pcrmentioning

confidence: 99%

STING Protects Against Cardiac Dysfunction and Remodelling by Blocking Autophagy

Xiong

Liu

et al. 2021

Preprint

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Background: Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods: In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway.Results: In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757.Conclusion: STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure.

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Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

Abstract: 1. Cytosolic DNA-STING-NLRP3 axis contributes to LPS-induced acute lung injury. 2. TLR4 isessential for the activation of cGAS-STING pathway in macrophages stimulated by LPS. 3. LPS stimulation couldenhance the transcriptional activation of STING via c-Mycinmacrophages.

Cited by 161 publications

References 47 publications

Mangiferin Mitigates Lipopolysaccharide-Induced Lung Injury by Inhibiting NLRP3 Inflammasome Activation

Mangiferin Mitigates Lipopolysaccharide-Induced Lung Injury by Inhibiting NLRP3 Inflammasome Activation

Mitochondrial DNA‐Mediated Inflammation in Acute Kidney Injury and Chronic Kidney Disease

STING Protects Against Cardiac Dysfunction and Remodelling by Blocking Autophagy

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