scholarly journals Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts

2021 ◽  
Vol 12 ◽  
Author(s):  
Sohee Lee ◽  
Jiha Shin ◽  
Jong-Seok Kim ◽  
Jongdae Shin ◽  
Sung Ki Lee ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Mammalian Target Of Rapamycin ◽  
Biological Significance ◽  
Inflammasome Activation ◽  
Human Trophoblast ◽  
Physiological Processes ◽  
Nlrp3 Inflammasome Activation ◽  
Placental Inflammation ◽  
Adverse Pregnancy ◽  
Underlying Mechanisms

Pathological maternal inflammation and abnormal placentation contribute to several pregnancy-related disorders, including preterm birth, intrauterine growth restriction, and preeclampsia. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, has been implicated in the regulation of various physiological processes, including innate immune response, autophagy, and cell growth. However, the relevance of TBK1 in the placental pro-inflammatory environment has not been investigated. In this study, we assessed the effect of TBK1 inhibition on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human trophoblast cell lines and mouse placenta. TBK1 phosphorylation was upregulated in the trophoblasts and placenta in response to LPS. Pharmacological and genetic inhibition of TBK1 in trophoblasts ameliorated LPS-induced NLRP3 inflammasome activation, placental inflammation, and subsequent interleukin (IL)-1 production. Moreover, maternal administration of amlexanox, a TBK1 inhibitor, reversed LPS-induced adverse pregnancy outcomes. Notably, TBK1 inhibition prevented LPS-induced NLRP3 inflammasome activation by targeting the mammalian target of rapamycin complex 1 (mTORC1). Thus, this study provides evidence for the biological significance of TBK1 in placental inflammation, suggesting that amlexanox may be a potential therapeutic candidate for treating inflammation-associated pregnancy-related complications.

IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis

2020 ◽  
Vol 27 (1) ◽  
pp. 84-93
Author(s):  
Yuan Li ◽  
Hongxia Chu ◽  
Mingsheng Zhao ◽  
Chaoze Li ◽  
Yetong Guan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Transcriptional Profiling ◽  
Inflammasome Activation ◽  
Downstream Effector ◽  
Nlrp3 Inflammasome Activation ◽  
Polymerase Chain ◽  
Underlying Mechanisms ◽  
And Control ◽  
Nlrp3 Expression

Abstract Background Interleukin-37 (IL-37) is a new negative immune regulator. It has 5 splicing forms, IL-37a–e, and most research mainly focuses on IL-37b functions in diverse diseases. Our previous research found that IL-37d inhibits lipopolysaccharide-induced inflammation in endotoxemia through a mechanism different from that of IL-37b. However, whether IL-37d plays a role in colitis and the underlying mechanisms is still obscure. Herein, we identified whether IL-37d regulates NLRP3 inflammasome activity and determined its effect on colitis. Methods NLRP3 inflammasome in macrophages from IL-37d transgenic (IL-37dtg) and control wild type (WT) mice were activated by lipopolysaccharide and adenosine 5′-triphosphate. The expression of NLRP3 inflammasome components and its downstream effector, IL-1β, were detected by real-time polymerase chain reaction, western blot, and ELISA. The models of alum-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis were used to investigate the function of IL-37d on regulating the activity of NLRP3 inflammasome in vivo. Results Our results showed that the activation of NLRP3 inflammasome in macrophage and alum-induced peritonitis was inhibited by IL-37d. Strikingly, IL-37d suppressed NLRP3 expression at the priming step via inhibiting NF-κB activation by transcriptional profiling. Moreover, the recombinant protein IL-37d attenuated NLRP3 inflammasome activation and the production of IL-1β, which could be reversed by IL-1R8 knockdown. Finally, IL-37d transgenic mice resisted DSS-induced acute colitis and NLRP3 inflammasome activation. Conclusion Interleukin-37d inhibits overactivation of the NLRP3 inflammasome through regulating NLRP3 transcription in an IL-1R8 receptor-mediated signaling pathway.

scholarly journals Inhibitory Effect and Mechanism of Arctium lappa Extract on NLRP3 Inflammasome Activation

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Young-Kyu Kim ◽  
Sushruta Koppula ◽  
Do-Wan Shim ◽  
Eun-Jung In ◽  
Su-Bin Kwak ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Biological Activities ◽  
Inhibitory Effect ◽  
Inflammasome Activation ◽  
Inhibitory Effects ◽  
Arctium Lappa ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Peritonitis Model

Arctium lappa (A. lappa), Compositae, is considered a potential source of nutrition and is used as a traditional medicine in East Asian countries for centuries. Although several studies have shown its biological activities as an anti-inflammatory agent, there have been no reports on A. lappa with regard to regulatory role in inflammasome activation. The purpose of this study was to investigate the inhibitory effects of A. lappa extract (ALE) on NLRP3 inflammasome activation and explore the underlying mechanisms. We found that ALE inhibited IL-1β secretion from NLRP3 inflammasome activated bone marrow derived macrophages but not that secreted by NLRC4 and AIM2 inflammasomes activation. Mechanistic studies revealed that ALE suppressed the ATPase activity of purified NLRP3 and reduced mitochondrial reactive oxygen species (mROS) generated during NLRP3 activation. Therefore, the inhibitory effect of ALE on NLRP3 inflammasome might be attributed to its ability to inhibit the NLRP3 ATPase function and attenuated the mROS during inflammasome activation. In addition, ALE significantly reduced the LPS-induced increase of plasma IL-1β in mouse peritonitis model. These results provide evidence of novel anti-inflammatory mechanisms of A. lappa, which might be used for therapeutic applications in the treatment of NLRP3 inflammasome-associated inflammatory disorders.

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.

scholarly journals SIRT1 Alleviates LPS-Induced IL-1β Production by Suppressing NLRP3 Inflammasome Activation and ROS Production in Trophoblasts

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 728 ◽  
Author(s):  
Sumi Park ◽  
Jiha Shin ◽  
Jeongyun Bae ◽  
Daewon Han ◽  
Seok-Rae Park ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intrauterine Growth Restriction ◽  
First Trimester ◽  
Inflammasome Activation ◽  
Class Iii ◽  
Potential Therapeutic Target ◽  
Maternal Inflammation ◽  
Cellular Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Emerging evidence indicates that aberrant maternal inflammation is associated with several pregnancy-related disorders such as preeclampsia, preterm birth, and intrauterine growth restriction. Sirtuin1 (SIRT1), a class III histone deacetylase, is involved in the regulation of various physiopathological processes including cellular inflammation and metabolism. However, the effect of SIRT1 on the placental proinflammatory environment remains to be elucidated. In this study, we investigated the effect of SIRT1 on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human first-trimester trophoblasts (Sw.71 and HTR-8/SVneo cells). Treatment with LPS elevated SIRT1 expression and induced NLRP3 inflammasome activation in mouse placental tissues and human trophoblasts. Knockdown of SIRT1 enhanced LPS-induced NLRP3 inflammasome activation, inflammatory signaling, and subsequent interleukin (IL)-1β secretion. Furthermore, knockdown of NLRP3 considerably attenuated the increase of IL-1β secretion in SIRT1-knockdown cells treated with LPS. Moreover, SIRT1 inhibited LPS-induced NLRP3 inflammasome activation by reducing oxidative stress. This study revealed a novel mechanism via which SIRT1 exerts anti-inflammatory effects, suggesting that SIRT1 is a potential therapeutic target for the prevention of inflammation-associated pregnancy-related complications.

scholarly journals Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Ahmad Alatshan ◽  
Szilvia Benkő
Keyword(s):  
Immune Responses ◽  
Nuclear Receptors ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Inflammatory Conditions ◽  
Physiological Processes ◽  
Nlrp3 Inflammasome Activation ◽  
Wide Range ◽  
Multiple Levels ◽  
Approved Drugs

Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.

scholarly journals Orientin Ameliorates LPS-Induced Inflammatory Responses through the Inhibitory of the NF-κB Pathway and NLRP3 Inflammasome

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Qingfei Xiao ◽  
Zhihui Qu ◽  
Ying Zhao ◽  
Liming Yang ◽  
Pujun Gao
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Raw 264.7 Cells ◽  
Prostaglandin E ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Inflammation is a complex response to diverse pathological conditions, resulting in negative rather than protective effects when uncontrolled. Orientin (Ori), a flavonoid component isolated from natural plants, possesses abundant properties. Thus, we aimed to discover the potential therapeutic effects of orientin on lipopolysaccharide- (LPS-) induced inflammation in RAW 264.7 cells and the underlying mechanisms. In our studies, we evaluated the effects of Ori on proinflammatory mediator production stimulated by LPS, including tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-18, and IL-1β, along with prostaglandin E2 (PGE2) and NO. Our data indicated that orientin dramatically inhibited the levels of these mediators. Consistent with these results, the expression levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were also reduced. Further study demonstrated that such inhibitory effects of Ori were due to suppression of the nuclear factor-kappa B (NF-κB) pathway and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) inflammasome activation, which may contribute to its anti-inflammatory effects. Together, these findings show that Ori may be an effective candidate for ameliorating LPS-induced inflammatory responses.

scholarly journals A Novel Mechanism of Mesenchymal Stromal Cell-Mediated Protection against Sepsis: Restricting Inflammasome Activation in Macrophages by Increasing Mitophagy and Decreasing Mitochondrial ROS

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Shuang Li ◽  
Hao Wu ◽  
Dong Han ◽  
Sai Ma ◽  
Wensi Fan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Cecal Ligation ◽  
Inflammasome Activation ◽  
Beneficial Effects ◽  
Caspase 1 ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Sepsis, a systemic inflammatory response to infection, is the leading cause of death in the intensive care unit (ICU). Previous studies indicated that mesenchymal stromal cells (MSCs) might have therapeutic potential against sepsis. The current study was designed to investigate the effects of MSCs on sepsis and the underlying mechanisms focusing on inflammasome activation in macrophages. The results demonstrated that the bone marrow-derived mesenchymal stem cells (BMSCs) significantly increased the survival rate and organ function in cecal ligation and puncture (CLP) mice compared with the control-grouped mice. BMSCs significantly restricted NLRP3 inflammasome activation, suppressed the generation of mitochondrial ROS, and decreased caspase-1 and IL-1β activation when cocultured with bone marrow-derived macrophages (BMDMs), the effects of which could be abolished by Mito-TEMPO. Furthermore, the expression levels of caspase-1, IL-1β, and IL-18 in BMDMs were elevated after treatment with mitophagy inhibitor 3-MA. Thus, BMSCs exert beneficial effects on inhibiting NLRP3 inflammasome activation in macrophages primarily via both enhancing mitophagy and decreasing mitochondrial ROS. These findings suggest that restricting inflammasome activation in macrophages by increasing mitophagy and decreasing mitochondrial ROS might be a crucial mechanism for MSCs to combat sepsis.

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 Natural Products that Target the NLRP3 Inflammasome to Treat Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Nan Ding ◽  
Bo Wei ◽  
Xiaohui Fu ◽  
Chuan Wang ◽  
Yimou Wu
Keyword(s):  
Natural Products ◽  
Nlrp3 Inflammasome ◽  
Inhibitory Effect ◽  
Easy Access ◽  
Inflammasome Activation ◽  
Multiple Organs ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms ◽  
Cellular Dysfunction ◽  
Broad Interest

Fibrosis is a common pathway followed by different organs after injury, and it can lead to parenchymal scarring, cellular dysfunction, and even organ failure. The NLRP3 inflammasome is a multiprotein complex composed of the sensor molecule NLRP3, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and the effector protease caspase-1. Overactivation of the NLRP3 inflammasome triggers the abundant secretion of IL-1β and IL-18, induces pyroptosis, and promotes the release of a swathe of proinflammatory proteins, all of which contribute to fibrogenic processes in multiple organs. In recent years, screening bioactive natural compounds for NLRP3 inhibitors to alleviate fibrosis has gained broad interest from the scientific community because of the associated cost-effectiveness and easy access. In this review, we systematically and comprehensively summarize the natural products, including terpenoids, phenols, and alkaloids, among others, and the plant-derived crude extracts, that have been reported to ameliorate fibrosis via inhibiting NLRP3 inflammasome activation and highlight the underlying mechanisms. Among all the compounds, diterpenoids is the most promising candidates for inhibiting NLRP3 inflammasome activation and improving fibrosis, as they possess combined inhibitory effect on NLRP3 inflammasome assembly and NF-κB signaling pathway. All the information may aid in the development of therapeutic strategies for the treatment of fibrotic diseases.

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