scholarly journals Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice

2020 ◽  
Vol 132 (6) ◽  
pp. 1503-1515 ◽  
Author(s):  
Ming Zhong ◽  
Wei Wu ◽  
Yingqin Wang ◽  
Hailei Mao ◽  
Jieqiong Song ◽  
...  
Keyword(s):  
Lung Injury ◽  
Healthy Volunteers ◽  
Mrna Expression ◽  
Nlrp3 Inflammasome ◽  
Cecal Ligation ◽  
Lung Injury Score ◽  
Blue Dye ◽  
Inflammasome Activation ◽  
Myeloperoxidase Activity ◽  
Nlrp3 Inflammasome Activation

Abstract Background Sepsis is the overwhelming inflammatory response to infection, in which nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role. Shingosine-1-phosphate is reported to evoke NLRP3 inflammasome activation. Sphingosine kinase 1 (SphK1) is the major kinase that catalyzes bioactive lipid shingosine-1–phosphate formation and its role in sepsis remains uncertain. The authors hypothesize that SphK1 elicits NLRP3 inflammasome activation and exacerbates sepsis. Methods Peripheral blood mononuclear cells were isolated from septic patients and healthy volunteers to measure messenger RNA (mRNA) expression. In mice, sepsis was induced by cecal ligation and puncture. Bone marrow–derived macrophages were prepared from C57BL/6J wild-type, Casp1−/−, Nlrp3−/− and SphK1−/− mice. PF-543 was used as the specific inhibitor of SphK1. Mortality, peripheral perfusion, lung Evan’s blue dye index, lung wet/dry ratio, lung injury score, lung myeloperoxidase activity, NLRP3 activation, and function of endothelial adherens junction were measured. Results SphK1 mRNA expression was higher in cells from septic patients versus healthy volunteers (septic patients vs. healthy volunteers: 50.9 ± 57.0 fold change vs. 1.2 ± 0.1 fold change, P < 0.0001) and was positively correlated with IL-1β mRNA expression in these cells (r = 0.537, P = 0.012) and negatively correlated with PaO2/Fio2 ratios (r = 0.516, P = 0.017). In mice that had undergone cecal ligation and puncture, the 5-day mortality was 30% in PF-543–treated group and 80% in control group (n = 10 per group, P = 0.028). Compared with controls, PF-543–treated mice demonstrated improved peripheral perfusion and alleviated extravascular Evan’s blue dye effusion (control vs. PF-543: 25.5 ± 3.2 ng/g vs. 18.2 ± 1.4 ng/g, P < 0.001), lower lung wet/dry ratio (control vs. PF-543: 8.0 ± 0.2 vs. 7.1 ± 0.4, P < 0.0001), descending lung injury score, and weaker lung myeloperoxidase activity. Inhibition of SphK1 suppressed caspase-1 maturation and interleukin-1β release through repressing NLRP3 inflammasome activation, and subsequently stabilized vascular endothelial cadherin through suppressing interleukin-1β–evoked Src-mediated phosphorylation of vascular endothelial cadherin. Conclusions SphK1 plays a crucial role in NLRP3 inflammasome activation and contributes to lung injury and mortality in mice polymicrobial sepsis. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Salidroside Attenuates Ventilation Induced Lung Injury via SIRT1-Dependent Inhibition of NLRP3 Inflammasome

2017 ◽  
Vol 42 (1) ◽  
pp. 34-43 ◽  
Author(s):  
Yan Wang ◽  
Chu-Fan Xu ◽  
Yu-Jian Liu ◽  
Yan-Fei Mao ◽  
Zhou Lv ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Cyclic Stretch ◽  
Mouse Lung ◽  
Control Group ◽  
Blue Dye ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Ventilation Induced Lung Injury

Background: Salidroside (SDS) is the main effective ingredient of Rhodiola rosea L with a variety of pharmacologic properties. We aim to investigate the effects of SDS on ventilation induced lung injury (VILI) and explore the possible underlying molecular mechanism. Methods: Lung injury was induced in male ICR mice via mechanical ventilation (30 ml/kg) for 4h. The mice were divided in four groups:(1) Control group; (2) Ventilation group; (3) SDS group; (4) Ventilation with SDS group. SDS (50 mg/kg) was injected intraperitoneally 1h before operation. Mouse lung vascular endothelial cells (MLVECs) were subjected to cyclic stretch for 4h. Results: It was found that SDS attenuated VILI as shown in HE staining, cell count and protein content levels in BAL fluid, W/D and Evans blue dye leakage into the lung tissue. SDS treatment inhibited the activation of NLRP3 inflammasome and subsequent caspase-1 cleavage as well as interleukin (IL)-1β secretion both in vivo and in vitro. Moreover, SDS administration up-regulated SIRT1 expression. Importantly, knockdown of SIRT1 reversed the inhibitory effect of SDS on NLRP3 inflammasome activation. Conclusions: Taken together, these findings indicate that SDS may confer protection against ventilation induced lung injury via SIRT1-de-pendent inhibition of NLRP3 inflammasome activation.

scholarly journals Overexpression of Limb Bud and Heart Alleviates Sepsis-Induced Acute Lung Injury via Inhibiting the NLRP3 Inflammasome

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yifan Wang ◽  
Yang Shi ◽  
Xiaohong Zhang ◽  
Jing Fu ◽  
Feng Chen
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Proinflammatory Cytokine ◽  
A549 Cells ◽  
Limb Bud ◽  
Lung Injury Score ◽  
Inflammasome Activation ◽  
Injury Score ◽  
Nlrp3 Inflammasome Activation

Objective. Sepsis is a leading cause of acute lung injury (ALI). This study attempted to investigate the effects of limb bud and heart (LBH) on the development of sepsis-induced ALI and its underlying mechanism of action. Methods. The sepsis-induced ALI mouse model was established by cecal ligation and puncture (CLP). The lung injury score and lung wet/dry weight (W/D) ratio were used to evaluate the lung injury. In vitro, ALI was simulated by lipopolysaccharide (LPS) treatment in A549 cells. The mRNA expression of LBH, NLRP3, ASC, and proinflammatory cytokines was measured by qRT-PCR. The viability of LPS-induced A549 cells was analyzed by MTT assay. Furthermore, western blot was performed to detect the protein expression of LBH, NLRP3, and ASC. LPS-induced A549 cells were treated with MCC950 (NLRP3 inflammasome inhibitor) to confirm the effect of LBH on NLRP3 inflammasome. Results. The mRNA and protein expression of LBH was decreased in sepsis-induced ALI. LBH overexpression reduced the lung injury score, lung W/D ratio, expression of proinflammatory cytokines, and NLRP3 inflammasome activation in sepsis-induced ALI mouse model. Additionally, LBH upregulation increased the viability, while it decreased the proinflammatory cytokine expression and NLRP3 inflammasome activation of LPS-induced A549 cells. Moreover, MCC950 reversed the promoting effects of LBH silencing on proinflammatory cytokine expression and NLRP3 inflammasome activation in LPS-induced A549 cells. Conclusions. LBH alleviated lung injury in sepsis-induced ALI mouse model by inhibiting inflammation and NLRP3 inflammasome, and restrained the inflammation by inhibiting NLRP3 inflammasome in LPS-induced A549 cells, providing a novel therapeutic target for ALI.

scholarly journals SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pan Pan ◽  
Miaomiao Shen ◽  
Zhenyang Yu ◽  
Weiwei Ge ◽  
Keli Chen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Cultured Cells ◽  
Inflammatory Responses ◽  
Specific Inhibitor ◽  
Inflammasome Activation ◽  
N Protein ◽  
Distinct Mechanism ◽  
Nlrp3 Inflammasome Activation ◽  
Proinflammatory Responses

AbstractExcessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

scholarly journals A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Jie Zheng ◽  
Lu Yao ◽  
Yijing Zhou ◽  
Xiaoqun Gu ◽  
Can Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Atopic Dermatitis ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
Nlrp3 Inflammasome ◽  
Myeloid Cells ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Mice Model ◽  
Nlrp3 Inflammasome Activation

AbstractAtopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)−33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been mostly described in myeloid cells that to mediate inflammasome activation conducted proinflammatory cytokine production of the IL-1 family. However, the role of NLRP3 inflammasome in the pathogenesis of AD, as well as IL-33 processing are highly controversial. Whether NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD has remained unclear. In this article, we found the mRNA expression of Il33 and Nlrp3 were notably increased in the lesional skin of AD patients compared to healthy controls. We then found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of MC903-mediated AD mice model, but no changes were observed for Il36α, Il36γ, Il1β, or Il18 mRNA expression, as well as IL-1β or IL-18 production. Overexpression of NLRP3 in human immortalized epithelial cells increased IL-33 expression, whereas siRNA targeting NLRP3 abolished IL-33 expression. In addition, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 showed no effect on the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 predominantly located in the nucleus of epithelial cells, which could directly bind to Il33 specific-promoters and transactivate it through an interaction with transcription factor IRF4. Furthermore, NLRP3 deficient mice exhibited a significant alleviated epidermis inflammation and decreased mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. Our results demonstrate a novel ability of NLRP3 to function as a crucial transcription factor of IL-33 in epithelium independently of inflammasome that to mediate the pathological process of AD.

scholarly journals Extracellular mitochondrial DNA promote NLRP3 inflammasome activation and induce acute lung injury through TLR9 and NF-κB

2019 ◽  
Vol 11 (11) ◽  
pp. 4816-4828 ◽  
Author(s):  
Guannan Wu ◽  
Qingqing Zhu ◽  
Junli Zeng ◽  
Xiaoling Gu ◽  
Yingying Miao ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Anemoside B4 Protects against Acute Lung Injury by Attenuating Inflammation through Blocking NLRP3 Inflammasome Activation and TLR4 Dimerization

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Renyikun Yuan ◽  
Jia He ◽  
Liting Huang ◽  
Li-Jun Du ◽  
Hongwei Gao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Macrophage Cells ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Acute lung injury (ALI) is an acute inflammatory process in the lung parenchyma. Anemoside B4 (B4) was isolated from Pulsatilla, a plant-based drug against inflammation and commonly applied in traditional Chinese medicine. However, the anti-inflammatory effect and the mechanisms of B4 are not clear. In this study, we explored the potential mechanisms and anti-inflammatory activity of B4 both in vitro and in vivo. The results indicated that B4 suppressed the expression of iNOS, COX-2, NLRP3, caspase-1, and IL-1β. The ELISA assay results showed that B4 significantly restrained the release of inflammatory cytokines like TNF-α, IL-6, and IL-1β in macrophage cells. In addition, B4 rescued mitochondrial membrane potential (MMP) loss in (lipopolysaccharide) LPS plus ATP stimulated macrophage cells. Co-IP and molecular docking results illustrated that B4 disrupted the dimerization of TLR4. For in vivo results, B4 exhibited a protective effect on LPS and bleomycin- (BLM-) induced ALI in mice through suppressing the lesions of lung tissues, the release of inflammatory cytokines, and the levels of white blood cells, neutrophils, and lymphoid cells in the blood. Collectively, B4 has a protective effect on ALI via blocking TLR4 dimerization and NLRP3 inflammasome activation, suggesting that B4 is a potential agent for the treatment of ALI.

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