The Supportive Role of NSC328382, a P2X7R Antagonist, in Enhancing the Inhibitory Effect of CRID3 on NLRP3 Inflammasome Activation in Rats with Dextran Sodium Sulfate-Induced Colitis

Mycobacterium tuberculosis(Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1βand TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

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Faculty Opinions recommendation of The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735165969.793559816 ◽

2019 ◽

Author(s):

Paras Anand

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Cysteine Cathepsins ◽

Nlrp3 Inflammasome Activation

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The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

Mediators of Inflammation ◽

10.1155/2013/678627 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 48

Author(s):

Elisa Benetti ◽

Fausto Chiazza ◽

Nimesh S. A. Patel ◽

Massimo Collino

Keyword(s):

Chronic Inflammation ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Metabolic Inflammation ◽

Nlrp3 Inflammasome Activation ◽

Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

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The role of NLRP3 inflammasome activation in radiation damage

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.109217 ◽

2019 ◽

Vol 118 ◽

pp. 109217 ◽

Cited By ~ 6

Author(s):

Jinlong Wei ◽

Heru Wang ◽

Huanhuan Wang ◽

Bin Wang ◽

Lingbin Meng ◽

...

Keyword(s):

Radiation Damage ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjw219 ◽

2016 ◽

pp. jjw219 ◽

Cited By ~ 21

Author(s):

Ling Liu ◽

Ying Dong ◽

Mei Ye ◽

Shi Jin ◽

Jianbo Yang ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Pathogenic Role ◽

Nlrp3 Inflammasome Activation ◽

Bowel Diseases ◽

Inflammatory Bowel

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NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/6057609 ◽

2017 ◽

Vol 2017 ◽

pp. 1-18 ◽

Cited By ~ 32

Author(s):

Merry W. Ma ◽

Jing Wang ◽

Krishnan M. Dhandapani ◽

Darrell W. Brann

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Nadph Oxidase ◽

Nlrp3 Inflammasome ◽

Healing Process ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Nadph Oxidase 2

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1β (IL-1β), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.

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The role of HIF-1α in regulating NLRP3 inflammasome activation in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17028 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17028-e17028 ◽

Cited By ~ 1

Author(s):

Yuan-Ru Chen ◽

Hsin-Chih Yeh ◽

Fang-Yen Chiu ◽

Hsin-En Wu ◽

Huei-Chen Fang ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Cancer Cells ◽

Nlrp3 Inflammasome ◽

Migration And Invasion ◽

Inflammasome Activation ◽

T24 Cells ◽

Nlrp3 Inflammasome Activation ◽

Bladder Cancer Cells

e17028 Background: Bladder cancer is one of the most common malignancies of urinary system with the forth incidence rate and the eighth leading mortality rate in male genitourinary tumors. Hypoxia environment activates the hypoxia‐signalling pathway, principally via hypoxia‐inducible transcription factors (HIF) to activate numerous target genes which mediate embryonic vascularization, metabolism, tumor angiogenesis and the other processes to supply tissues with blood and oxygen. Inflammasomes are multiprotein signal responsible for the maturation of proinflammatory cytokines IL-1β and IL-18 as well as trigger the inflammatory cell pyroptosis. Recent study showed that HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. However, the role of HIF1α in regulating the progression of bladder cancer has not been examined so far. The present study aimed to investigate the effect of HIF-1α on NLRP3 inflammasome activation in urothelial carcinoma. Methods: In this research, urothelial carcinoma cell lines were treated with NLRP3 inflammasome inducers, LPS/ATP, to induce NLRP3 inflammasome activation. Results: Our preliminary results showed that both T24 and 5637 bladder cancer cells can be induced NLRP3 inflammasome activation and IL-1β secretion. In addition, hypoxia also induces the secretion of IL-1β in T24 cells. We further investigated the effect of NLRP3 inflammasome activation in modulating EMT-related protein levels, migration and invasion in bladder cancer T24 cells. Our results demonstrated that NLRP3 inflammasome activation promotes tumor growth and metastasis in bladder cancer cells. Furthermore, knockdown of HIF1α reduces both inflammatory response and migratory activity in bladder cancer. Conclusions: Collectively, these results suggest that targeting NLRP3 inflammasome might offer potential to treat hypoxic malignant tumor in bladder carcinoma.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6346734 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

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.

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