scholarly journals Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis

2019 ◽  
Vol 20 (2) ◽  
pp. 360 ◽  
Author(s):  
Xi-Chun Pan ◽  
Ya Liu ◽  
Yan-Yan Cen ◽  
Ya-Lan Xiong ◽  
Jing-Mei Li ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Dual Role ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Collagen Production ◽  
Antifibrotic Effect ◽  
Myeloid Differentiation Factor

In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson’s staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1β maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-β1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFβ1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis.

scholarly journals Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Yufei Luo ◽  
Bojun Xiong ◽  
Haiping Liu ◽  
Zehong Chen ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Mechanistic Study ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

CLEC5A knockdown protects against the cardiac dysfunction after Myocardial infarction by suppressing macrophage polarization, NLRP3 inflammasome activation and pyroptosis

2021 ◽  
Author(s):  
Xin Wang ◽  
Yu Hu ◽  
Yaguang Wang ◽  
Dapeng Shen ◽  
Guizhou Tao
Keyword(s):  
Myocardial Infarction ◽  
Nlrp3 Inflammasome ◽  
Cardiac Dysfunction ◽  
Macrophage Polarization ◽  
Left Ventricular ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
M1 Polarization

Increasing evidence has shown that NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptotic cell death play vital roles in the pathophysiology of myocardial infarction (MI), a common cardiovascular disease characterized with cardiac dysfunction. C-type lectin member 5A (CLEC5A) is reported to strongly associate with activation of NLRP3 inflammasome and pyroptosis. In this study, in vivo MI model was established by the ligation of left anterior descending coronary artery on male C57BL/6 mice, and CLEC5A knockdown was further achieved by intra-myocardial injection of adenovirus delivering shRNA-CLEC5A. CLEC5A was found to be highly expressed in left ventricular of MI mice, while CLEC5A knockdown conversely alleviated the cardiac dysfunction in MI mice. Besides, MI-induced classical activation of macrophages was significantly inhibited after CLEC5A silencing. Additionally, CLEC5A knockdown dramatically inhibited MI-triggered activation of NLRP3 inflammasome, pyroptosis and NF-κB signaling in left ventricular of mice. In vitro experiment further validated that CLEC5A knockdown suppressed M1 polarization in LPS/IFNγ-stimulated RAW264.7 cells, and inhibited the polarized RAW264.7-induced activation of NLRP3 inflammasome/pyroptosis signaling in co-cultured cardiomyocytes. In conclusion, CLEC5A knockdown protects against the MI-induced cardiac dysfunction by regulating macrophage polarization, NLRP3 inflammasome and cell pyroptosis.

scholarly journals Omega-3FAs Can Inhibit the Inflammation and Insulin Resistance of Adipose Tissue Caused by HHcy Induced Lipids Profile Changing in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Li ◽  
Heng Zhang ◽  
Yongqiang Dong ◽  
Xian Wang ◽  
Guang Wang
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Lipids Profile

The adipose Nod-like receptor protein 3 (NLRP3) inflammasome initiates insulin resistance; however, the mechanism of inflammasome activation in adipose tissue remains elusive. In this study, homocysteine (Hcy) was found to participate in insulin resistance via a NLRP3 inflammasome-related process. Hcy-induced activation of NLRP3 inflammasomes were observed in adipose tissue during the generation of insulin resistance in vivo. This animal model suggests that diets high in omega-3 fatty acids alter serum and adipose lipid profiles, and in this way, omega-3 fatty acids may reduce adipose tissue inflammation and attenuate insulin resistance.

scholarly journals UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui Song ◽  
Chunyuan Zhao ◽  
Zhongxia Yu ◽  
Qizhao Li ◽  
Rongzhen Yan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Danger Signals ◽  
Nlrp3 Inflammasome Activation ◽  
Microbial Infections ◽  
Nlrp3 Expression

AbstractNOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation.

scholarly journals Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hyun Young Kim ◽  
Young Jae Choi ◽  
Sang Kyum Kim ◽  
Hyunsung Kim ◽  
Dae Won Jun ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanism ◽  
Kupffer Cell ◽  
Nlrp3 Inflammasome ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Underlying Mechanism ◽  
Receptor Protein ◽  
Antifibrotic Effect

AbstractDemand for a cure of liver fibrosis is rising with its increasing morbidity and mortality. Therefore, it is an urgent issue to investigate its therapeutic candidates. Liver fibrosis progresses following ‘multi-hit’ processes involving hepatic stellate cells, macrophages, and hepatocytes. The NOD-like receptor protein 3 (NLRP3) inflammasome is emerging as a therapeutic target in liver fibrosis. Previous studies showed that the anti-rheumatic agent auranofin inhibits the NLRP3 inflammasome; thus, this study evaluates the antifibrotic effect of auranofin in vivo and explores the underlying molecular mechanism. The antifibrotic effect of auranofin is assessed in thioacetamide- and carbon tetrachloride-induced liver fibrosis models. Moreover, hepatic stellate cell (HSC), bone marrow-derived macrophage (BMDM), kupffer cell, and hepatocyte are used to examine the underlying mechanism of auranofin. Auranofin potently inhibits activation of the NLRP3 inflammasome in BMDM and kupffer cell. It also reduces the migration of HSC. The underlying molecular mechanism was inhibition of cystine-glutamate antiporter, system Xc. Auranofin inhibits system Xc activity and instantly induced oxidative burst, which mediated inhibition of the NLRP3 inflammasome in macrophages and HSCs. Therefore, to the best of our knowledge, we propose the use of auranofin as an anti-liver fibrotic agent.

scholarly journals Cicadidae Periostracum Attenuates Atopic Dermatitis Symptoms and Pathology via the Regulation of NLRP3 Inflammasome Activation

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Gunhyuk Park ◽  
Byeong Cheol Moon ◽  
Seung Mok Ryu ◽  
Wook Jin Kim ◽  
Hye-Sun Lim
Keyword(s):  
Atopic Dermatitis ◽  
House Dust ◽  
House Dust Mite ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Dust Mite

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease of complex etiology. Despite its increasing prevalence, treatment for AD is still limited. Crude drugs, including herbal extracts or natural resources, are being used to treat AD symptoms, with minimum side effects. Cicadidae Periostracum (CP), derived from the slough of insects belonging to the family Cicadidae, is a commonly used crude drug in traditional Asian medicine to treat/control epilepsy, shock, and edema. However, the effect of CP on AD-like skin lesions is unknown. In this study, we examined the effect of a CP water extract on AD disease development in vivo, using a house dust mite-induced AD mouse model, and in vitro, using HaCaT keratinocytes and a 3D human skin equivalent system. Importantly, CP administration alleviated house dust mite-induced AD-like symptoms, suggested by the quantified dermatitis scores, animal scratching behaviors, skin moisture retention capacity, and skin lesion and ear thickness. Furthermore, histopathological analysis demonstrated that CP decreased intralesional mast cell infiltration. In addition, CP treatments decreased the systemic levels of immunoglobulin E, histamine, and thymic stromal lymphopoietin (TSLP) and the local mRNA expression of TSLP and several Th1/Th2 cytokines. Our data suggest that these effects were mediated by the inhibition of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation. In vivo and in vitro CP treatments resulted in the downregulation of inflammasome components, such as ASC and cleaved caspase-1, as well as related mediators such as IL-1β and reactive oxygen species. Collectively, our results suggest that CP is a potential therapeutic agent for AD, controlling inflammatory responses through the suppression of NLRP3 inflammasome activation.

scholarly journals H3 Relaxin Alleviates Migration, Apoptosis and Pyroptosis Through P2X7R-Mediated Nucleotide Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation in Retinopathy Induced by Hyperglycemia

2020 ◽  
Vol 11 ◽  
Author(s):  
Kelaier Yang ◽  
Jiannan Liu ◽  
Xiaohui Zhang ◽  
Ziqi Ren ◽  
Lei Gao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Sprague Dawley ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms ◽  
And Migration

Introduction: P2X7R excitation-interrelated NLRP3 inflammasome activation induced by high glucose contributes to the pathogenesis of diabetic retinopathy (DR). Relaxin-3 is a bioactive peptide with a structure similar to insulin, which has been reported to be effective in diabetic cardiomyopathy models in vivo and in vitro. However, it is not known whether relaxin-3 has a beneficial impact on DR, and the underlying mechanisms of the effect are also remain unknown.Methods and Results: The retinas of male streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were characterized. Human retinal microvascular endothelial cells (HRMECs) were used to evaluate the anti-inflammatory, antiapoptotic, antipyroptotic and anti-migration effects of H3 relaxin by transmission electron microscopy, wound-healing assay, transwell assay, flow cytometry, cytokine assays and western-blot analysis. After H3 relaxin treatment, changes of the ultrastructure and expression of NLRP3 inflammasome related proteins in the retinas of rats were compared with those in the diabetic group. In vitro, H3 relaxin played a beneficial role that decreased cell inflammation, apoptosis, pyroptosis and migration stimulated by advanced glycation end products (AGEs). Moreover, inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury that similar to the effects of H3 relaxin. H3 relaxin suppressed the stimulation of apoptosis, pyroptosis and migration of HRMECs in response to AGEs mediated by P2X7R activation of the NLRP3 inflammasome.Conclusion: Our findings provide new insights into the mechanisms of the inhibitory effect of H3 relaxin on AGE-induced retinal injury, including migration, apoptosis and pyroptosis, mediated by P2X7R-dependent activation of the NLRP3 inflammasome in HRMECs.

scholarly journals The Role of Melatonin on NLRP3 Inflammasome Activation in Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1020
Author(s):  
Burak Ibrahim Arioz ◽  
Emre Tarakcioglu ◽  
Melis Olcum ◽  
Sermin Genc
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intracellular Signaling ◽  
Metabolic Diseases ◽  
Metabolic Stress ◽  
Clinical Importance ◽  
Rapid Identification ◽  
In Vivo Studies ◽  
Inflammasome Activation

NLRP3 inflammasome is a part of the innate immune system and responsible for the rapid identification and eradication of pathogenic microbes, metabolic stress products, reactive oxygen species, and other exogenous agents. NLRP3 inflammasome is overactivated in several neurodegenerative, cardiac, pulmonary, and metabolic diseases. Therefore, suppression of inflammasome activation is of utmost clinical importance. Melatonin is a ubiquitous hormone mainly produced in the pineal gland with circadian rhythm regulatory, antioxidant, and immunomodulatory functions. Melatonin is a natural product and safer than most chemicals to use for medicinal purposes. Many in vitro and in vivo studies have proved that melatonin alleviates NLRP3 inflammasome activity via various intracellular signaling pathways. In this review, the effect of melatonin on the NLRP3 inflammasome in the context of diseases will be discussed.

scholarly journals Up-Regulating Relaxin Expression by G-Quadruplex Interactive Ligand to Achieve Antifibrotic Action

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3692-3700 ◽  
Author(s):  
Hui-Ping Gu ◽  
Sen Lin ◽  
Ming Xu ◽  
Hai-Yi Yu ◽  
Xiao-Jun Du ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Gene Promoter ◽  
Binding Motif ◽  
Endogenous Expression ◽  
G Quadruplex

Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine. The G-rich sequences and the G-quadruplexes were localized adjacent to the binding motif of signal transducer and activator of transcription (STAT)3, which negatively regulates relaxin expression. Thus, we hypothesized that the formation and stabilization of G-quadruplexes by berberine could influence relaxin expression. We found that berberine-induced formation of G-quadruplexes did increase relaxin gene expression measured at mRNA and protein levels. Formation of G-quadruplexes significantly reduced STAT3 binding to the promoter of relaxin gene. This was associated with consequent increase in the binding of RNA polymerase II and STAT5a to relaxin gene promoter. In cardiac fibroblasts and rats treated with angiotensin II, berberine was found to suppress fibroblast activation, collagen synthesis, and extent of cardiac fibrosis through up-regulating relaxin. The antifibrotic action of berberine in vitro and in vivo was similar to that by exogenous relaxin. Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.

Sign in / Sign up

Export Citation Format

Share Document