High glutamate concentration reverses the inhibitory effect of microglial adenosine 2A receptor on NLRP3 inflammasome assembly and activation

2021 ◽  
pp. 136431
Author(s):  
Hao Du ◽  
Yan Tan ◽  
Chang-Hong Li ◽  
Yan Zhao ◽  
Ping Li ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inhibitory Effect ◽  
Glutamate Concentration ◽  
Adenosine 2A Receptor

Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS

Inflammasome ◽  
2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Xuesong Sang ◽  
Hongbin Wang ◽  
Yihui Chen ◽  
Qiuhong Guo ◽  
Ailing Lu ◽  
...  
Keyword(s):  
Vitamin C ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Protein Complexes ◽  
Inhibitory Effect ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Regulatory Effects

AbstractInflammasomes are intracellular protein complexes that mediate maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes have been connected with various diseases, therefore the regulation of inflammasome activation is important for the development of novel therapies for many inflammatory syndromes. Vitamin C is an essential nutrient and has regulatory effects on immune cells. Here we report that vitamin C has an inhibitory effect on the activation of the NLRP3 inflammasome in vitro and in vivo. Mechanistically, this inhibition is through scavenging mitochondrial ROS but not through NF-κB inhibition. Moreover, specificity tests show that the AIM2 inflammasome and the NLRC4 inflammasome can also be inhibited by vitamin C. Our results have thus identified a new inflammasome regulator and provide therapeutic potential for inflammasome-associated diseases.

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.

Dual Targeting of Autophagy and NF-κB Pathway by PPARγ Contributes to the Inhibitory Effect of Demethoxycurcumin on NLRP3 Inflammasome Priming

2021 ◽  
Vol 14 ◽  
Author(s):  
Jing Tang ◽  
Xiaoxue Tan ◽  
Xiangmi Huang ◽  
Jie Zhang ◽  
Liang Chen ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Nuclear Translocation ◽  
Inhibitory Effect ◽  
Caspase 1 ◽  
Dual Targeting ◽  
Transmission Electron ◽  
Subsequent Activation ◽  
Natural Derivative ◽  
Pparγ Expression

Background: Demethoxycurcumin (DMC), a natural derivative of curcumin, has anti-inflammatory activities. However, the mechanism has not been fully elucidated. Objective: The aim of the current study was to investigate the role of DMC on NLRP3 inflammasome priming. Methods: Protein expression was quantified by western blotting. Inflammatory cytokines were measured by ELISA. Autophagosomes were evaluated by transmission electron microscopy. Results: DMC inhibited LPS-stimulated NLRP3, pro-caspase-1, and pro-IL-1β expression. Meanwhile, DMC diminished NLRP3-dependent IL-1β maturation, caspase-1 activation, IL-1β and IL-18 production caused by LPS plus ATP. Moreover, DMC induced autophagy and autophagy inhibitor 3-MA abrogated the role of DMC on NLRP3 inflammasome priming and subsequent activation. DMC also inhibited LPS-stimulated phosphorylation and nuclear translocation of p65 NF-κB. Additionally, DMC significantly increased the PPARγ expression and the effects of DMC in NF-κB inhibition, autophagy, and NLRP3 inflammasome priming were abrogated by specific PPARγ antagonist T0070907. Conclusion: The evidence presented here has confirmed that DMC increases PPARγ expression, resulting in autophagy and NF-κB inhibition, and subsequently inhibits LPS-induced NLRP3 inflammasome priming and subsequent activation.

scholarly journals Mir-21 Mediates the Inhibitory Effect of Ang (1–7) on AngII-induced NLRP3 Inflammasome Activation by Targeting Spry1 in lung fibroblasts

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Na-Na Sun ◽  
Chang-Hui Yu ◽  
Miao-Xia Pan ◽  
Yue Zhang ◽  
Bo-Jun Zheng ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Nlrp3 Inflammasome ◽  
Lung Fibrosis ◽  
Collagen Synthesis ◽  
Inhibitory Effect ◽  
Lung Fibroblasts ◽  
Inflammasome Activation ◽  
Apoptosis Resistance ◽  
Nlrp3 Inflammasome Activation

AbstractMicroRNA-21 (mir-21) induced by angiotensin II (AngII) plays a vital role in the development of pulmonary fibrosis, and the NLRP3 inflammasome is known to be involved in fibrogenesis. However, whether there is a link between mir-21 and the NLRP3 inflammasome in pulmonary fibrosis is unknown. Angiotensin-converting enzyme 2/angiotensin(1–7) [ACE2/Ang(1–7)] has been shown to attenuate AngII-induced pulmonary fibrosis, but it is not clear whether ACE2/Ang(1–7) protects against pulmonary fibrosis by inhibiting AngII-induced mir-21 expression. This study’s aim was to investigate whether mir-21 activates the NLRP3 inflammasome and mediates the different effects of AngII and ACE2/Ang(1–7) on lung fibroblast apoptosis and collagen synthesis. In vivo, AngII exacerbated bleomycin (BLM)-induced lung fibrosis in rats, and elevated mir-21 and the NLRP3 inflammasome. In contrast, ACE2/Ang(1–7) attenuated BLM-induced lung fibrosis, and decreased mir-21 and the NLRP3 inflammasome. In vitro, AngII activated the NLRP3 inflammasome by up-regulating mir-21, and ACE2/Ang(1–7) inhibited NLRP3 inflammasome activation by down-regulating AngII-induced mir-21. Over-expression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry1, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts. These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang(1–7) on AngII-induced activation of the NLRP3 inflammasome by targeting Spry1 in lung fibroblasts.

scholarly journals NF-κB/ABCA1 Pathway Aggravates ox-LDL-Induced Cell Pyroptosis by Activation of NLRP3 Inflammasomes in THP-1-Derived Macrophages

2021 ◽  
Author(s):  
Jiashan Li ◽  
Jiaru Liu ◽  
Ying Yu ◽  
Yuee Liu ◽  
Xiuru Guan
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cholesterol Efflux ◽  
Inhibitory Effect ◽  
Chronic Inflammatory Disease ◽  
Control Group ◽  
Lipid Deposition ◽  
Double Positive ◽  
Nlrp3 Inflammasomes ◽  
First Time ◽  
The Relationship

Abstract There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease and characterized by lipid deposition in blood vessels. Pyroptosis, an inflammatory form of cell death by certain inflammasomes, has been shown to be associated with the development of AS in recent years. However, the relationship between lipid deposition in foam cells and cell pyroptosis has not been clarified. Here, we demonstrate that with increasing ox-LDL concentration, the expression of pyroptosis associated protein GSDMD, NLRP3 inflammasome gradually increased, intracellular LDH and mature IL-1β release increased, and the proportion of double positive cells with Hoechst/PI staining increased. Interestingly, the expression of NF-κB signal activation marker protein p-NF-κB and p-IκB increased with the increase of ox-LDL concentration. Ox-LDL-induced pyroptosis can be abolished by NF-κB phosphorylation inhibitor, BAY11-7082. Additionally, BAY11-7082 could also significantly up-regulate the protein expression of ABCA1 and eliminate the inhibitory effect of ox-LDL on the expression of ABCA1.Moreover, siABCA1 was transfected into THP-1-derived macrophages under ox-LDL treatment. Compared with the control group, the expression of GSDMD and NLRP3 inflammasome, the release of mature IL-1β and LDH increased, and the proportion of Hoechst/PI staining double-positive cells increased with blocked cholesterol efflux. Finally, cells treated with VX-765, a pyroptosis inhibitor, showed increased cholesterol efflux and cell foaming in THP-1-derived macrophages,which suggest that cell pyroptosis may be a "double-edged sword" in the development of AS. In conclusion,our findings demonstrate for the first time that the NF-κB/ABCA1 pathway is involved in ox-LDL induced pyroptosis by cholesterol efflux blocked activation of NLRP3 inflammasomes in THP-1-derived macrophages, providing a new therapeutic avenue for the prevention and treatment of AS.

scholarly journals 3β,23-Dihydroxy-12-ene-28-ursolic Acid Isolated from Cyclocarya paliurus Alleviates NLRP3 Inflammasome-Mediated Gout via PI3K-AKT-mTOR-Dependent Autophagy

2022 ◽  
Vol 2022 ◽  
pp. 1-15
Author(s):  
Dongxiao Lou ◽  
Xiaogai Zhang ◽  
Cuihua Jiang ◽  
Fang Zhang ◽  
Chao Xu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ursolic Acid ◽  
Nlrp3 Inflammasome ◽  
Soft Tissues ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Expression Level ◽  
Expression Ratio ◽  
Cyclocarya Paliurus ◽  
Caspase 1

Gout is regarded as a painful inflammatory arthritis induced by the deposition of monosodium urate crystals in joints and soft tissues. Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated IL-1β production plays a crucial role in the pathological process of gout. Cyclocarya paliurus (CP) tea was found to have an effect on reducing the blood uric acid level of people with hyperuricemia and gout. However, its medicinal ingredients and mechanism for the treatment of gout are still unclear. Thus, this study was designed to investigate the effects of the active triterpenoids isolated from C. paliurus on gout and explore the underlying mechanism. The results showed that compound 2 (3β,23-dihydroxy-12-ene-28-ursolic acid) from C. paliurus significantly decreased the protein expression of IL-1β, caspase-1, pro-IL-1β, pro-caspase-1, and NLRP3. Furthermore, the production of ROS in the intracellular was reduced after compound 2 treatment. However, ROS agonist rotenone remarkably reversed the inhibitory effect of compound 2 on the protein expression of NLRP3 inflammasome. Additionally, the expression level of LC3 and the ratio of LC3II/LC3I were increased, but the expression level of p62 was suppressed by compound 2 whereas an autophagy inhibitor 3-methyladenine (3-MA) significantly abolished the inhibitory effects of compound 2 on the generation of ROS and the protein expression of NLRP3 inflammasome. Moreover, compound 2 could ameliorate the expression ratio of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR. Interestingly, mTOR activator MHY-1485 could block the promotion effect of compound 2 on autophagy regulation and inhibitory effect of compound 2 on induction of ROS and IL-1β. In conclusion, these findings suggested that compound 2 may effectively improve NLRP3 inflammasome-mediated gout via PI3K-AKT-mTOR-dependent autophagy and could be further investigated as a potential agent against gout.

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