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 The Role of NLRP3 Inflammasome Activities in Bone Diseases and Vascular Calcification

Inflammation ◽  
2020 ◽  
Author(s):  
Chenyang Yu ◽  
Caihua Zhang ◽  
Zhihui Kuang ◽  
Qiang Zheng
Keyword(s):  
Vascular Calcification ◽  
Nlrp3 Inflammasome ◽  
Periodontal Diseases ◽  
Bone Destruction ◽  
Bone Diseases ◽  
Sterile Inflammation ◽  
Inflammatory Factors ◽  
Bone Homeostasis ◽  
Caspase 1

Abstract Continuous stimulation of inflammation is harmful to tissues of an organism. Inflammatory mediators not only have an effect on metabolic and inflammatory bone diseases but also have an adverse effect on certain genetic and periodontal diseases associated with bone destruction. Inflammatory factors promote vascular calcification in various diseases. Vascular calcification is a pathological process similar to bone development, and vascular diseases play an important role in the loss of bone homeostasis. The NLRP3 inflammasome is an essential component of the natural immune system. It can recognize pathogen-related molecular patterns or host-derived dangerous signaling molecules, recruit, and activate the pro-inflammatory protease caspase-1. Activated caspase-1 cleaves the precursors of IL-1β and IL-18 to produce corresponding mature cytokines or recognizes and cleaves GSDMD to mediate cell pyroptosis. In this review, we discuss the role of NLRP3 inflammasome in bone diseases and vascular calcification caused by sterile or non-sterile inflammation and explore potential treatments to prevent bone loss.

scholarly journals The Role of the Effects of Autophagy on NLRP3 Inflammasome in Inflammatory Nervous System Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Shizhen Zhao ◽  
Xiaotian Li ◽  
jie Wang ◽  
Honggang Wang
Keyword(s):  
Nervous System ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Hypoperfusion ◽  
Receptor Protein ◽  
Future Research ◽  
Nervous System Diseases ◽  
Caspase 1

Autophagy is a stable self-sustaining process in eukaryotic cells. In this process, pathogens, abnormal proteins, and organelles are encapsulated by a bilayer membrane to form autophagosomes, which are then transferred to lysosomes for degradation. Autophagy is involved in many physiological and pathological processes. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, containing NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1, can activate caspase-1 to induce pyroptosis and lead to the maturation and secretion of interleukin-1 β (IL-1 β) and IL-18. NLRP3 inflammasome is related to many diseases. In recent years, autophagy has been reported to play a vital role by regulating the NLRP3 inflammasome in inflammatory nervous system diseases. However, the related mechanisms are not completely clarified. In this review, we sum up recent research about the role of the effects of autophagy on NLRP3 inflammasome in Alzheimer’s disease, chronic cerebral hypoperfusion, Parkinson’s disease, depression, cerebral ischemia/reperfusion injury, early brain injury after subarachnoid hemorrhage, and experimental autoimmune encephalomyelitis and analyzed the related mechanism to provide theoretical reference for the future research of inflammatory neurological diseases.

Role of NLRP3-Inflammasome/Caspase-1/Galectin-3 Pathway on Atrial Remodeling in Diabetic Rabbits

2020 ◽  
Vol 13 (5) ◽  
pp. 731-740 ◽  
Author(s):  
Xiaohan Wu ◽  
Yang Liu ◽  
Daimiao Tu ◽  
Xianjian Liu ◽  
Shulin Niu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Atrial Remodeling ◽  
Caspase 1 ◽  
Galectin 3 ◽  
Diabetic Rabbits

scholarly journals Inhibition of IL-13 and IL-13Rα2 Expression by IL-32θ in Human Monocytic Cells Requires PKCδ and STAT3 Association

2019 ◽  
Vol 20 (8) ◽  
pp. 1949 ◽  
Author(s):  
Thu-Huyen Pham ◽  
Yesol Bak ◽  
Jae-Wook Oh ◽  
Jingi Hong ◽  
Seungyeoun Lee ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Nuclear Translocation ◽  
Inhibitory Effect ◽  
Additive Effects ◽  
Signal Transducer ◽  
Monocytic Cells ◽  
Kinase C ◽  
Direct Association ◽  
Transcription 3

Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.

Rapid Release of Interleukin-1β from Human Platelets Is Independent of NLRP3 and Caspase

2021 ◽  
Author(s):  
Gabrielle J. Pennings ◽  
Caroline J. Reddel ◽  
Mathew Traini ◽  
Magdalena Lam ◽  
Maaike Kockx ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Human Platelets ◽  
Interleukin 1Β ◽  
Enzyme Linked Immunosorbent Assay ◽  
Thrombin Receptor ◽  
Classical Pathway ◽  
Receptor Agonists ◽  
Caspase 1 ◽  
Rapid Release ◽  
Transmission Electron

Abstract Objective Platelets are critical in mediating both rapid responses to injury and the development and progression of coronary disease. Several studies have shown that, after prolonged exposure to agonists, they produce and release inflammatory mediators including interleukin-1β (IL-1β), via the classical pathway (NLRP3 inflammasome and caspase-1 cleavage to release active IL-1β) as described for leukocytes. This study aimed to determine whether there is rapid release of IL-1β in response to soluble platelet agonists and whether such rapid release is NLRP3- and caspase-1-dependent. Methods and Results Using flow cytometry to detect platelet activation (and release of α and dense granule contents) and the combination of Western blotting, enzyme-linked-immunosorbent assay, and immunogold labeling transmission electron and immunofluorescence microscopy, we identified that resting human platelets contain mature IL-1β. Platelets release IL-1β within minutes in response to adenosine diphosphate (ADP), collagen, and thrombin receptor agonists, but not in response to conventional NLRP3 inflammasome agonists—lipopolysaccharide and adenosine triphosphate. The rapid release of IL-1β in response to ADP and thrombin receptor agonists was independent of caspases (including caspase-1) and NLRP3. Immature and mature IL-1β were identified as low-abundance proteins on transmission electron microscopy of human platelets, and were localized to the platelet cytosol, open canalicular system, and the periphery of α granules. Conclusion Unlike monocytes and neutrophils, human platelets are capable of rapid agonist- and time-dependent release of IL-1β by a mechanism which is independent of caspase-1 and NLRP3.

Abstract 127: Txnip-Mediated NLRP3 Inflammasome Activation as a Novel Mechanism of Myocardial Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yi Liu ◽  
Lijian Zhang ◽  
Yan Qu ◽  
Chao Gao ◽  
Jingyi Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion

As an inhibitor of the antioxidant thioredoxin, thioredoxin-interacting protein (Txnip) is linked to insulin resistance. NLRP3 inflammasome, a major regulator of innate immunity, has been reported to be activated by Txnip, thus contributing to the pathogenesis of type 2 diabetes mellitus. However, the role of Txnip and its NLRP3 inflammasome activation in the myocardial ischemia/reperfusion (MI/R) injury has not been previously investigated. C57BL/6J mice were subjected to 30 min of ischemia and 3 or 24 hrs of reperfusion. The ischemic heart exhibited increased Txnip and NLRP3 expressions, increased interaction between Txnip and NLRP3 (by immunoprecipitation, 1.8-fold increase over sham), and increased IL-1β, IL-18 and caspase-1 expressions (%increase: 80%, 77% and 110%, respectively) (n=8, all P <0.05). Compared with vehicle group, those mice either receiving intramyocardial small-interfering RNA (siRNA) injection to specifically knockdown the myocardial NLRP3 or intraperitoneal injection of the inflammasome inhibitor (BAY 11-7082) exhibited significantly improved cardiac function (by 28% and 25%), decreased the infarct size (by 40% and 38%), and decreased the cardiomyocytes apoptosis (all P <0.05). NLRP3 knockdown or inflammasome inhibitor also decreased the inflammatory cells infiltration (macrophages and neutrophils) and cytokines (TNF-α, INF-γ and IL-6) production (all P <0.05). To elucidate the role of Txnip in the NLRP3 activation in MI/R, intramyocardial injection of Txnip siRNA was performed to specifically knockdown the myocardial Txnip expression. Compared with vehicle, the Txnip knockdown significantly decreased Txnip/NLRP3 interaction and NLRP3activation as evidenced by lower expressions of IL-1β and caspase-1, decreased inflammatory cells infiltration and cytokines expressions, and consequently decreased the myocardial infarct size and increased the heart function (all P <0.05). Collectively, we demonstrated for the first time that Txnip mediatedNLRP3 inflammasome activation is a novel mechanism of MI/R injury. Interventions targeted to blocking the activation of NLRP3 by inhibiting Txnip may have therapeutic potential for preventing MI/R injury.

NLRP3 inflammasome activation contributes to aldosterone-induced podocyte injury

2017 ◽  
Vol 312 (4) ◽  
pp. F556-F564 ◽  
Author(s):  
Mi Bai ◽  
Ying Chen ◽  
Min Zhao ◽  
Yue Zhang ◽  
John Ci-Jiang He ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Renal Tubules ◽  
Mineralocorticoid Receptor Antagonist ◽  
Podocyte Injury ◽  
Nlrp3 Gene ◽  
Caspase 1 ◽  
Focal Segmental Glomerular Sclerosis ◽  
Nlrp3 Inflammasome Activation

Aldosterone (Aldo) has been shown as an important contributor of podocyte injury. However, the underlying molecular mechanisms are still elusive. Recently, the pathogenic role of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in mediating renal tubular damage was identified while its role in podocyte injury still needs evidence. Thus the present study was undertaken to investigate the role of NLRP3 inflammasome in Aldo-induced podocyte damage. In vitro, exposure of podocytes to Aldo enhanced NLRP3, caspase-1, and IL-18 expressions in dose- and time-dependent manners, indicating an activation of NLRP3 inflammasome, which was significantly blocked by the mineralocorticoid receptor antagonist eplerenone or the antioxidant N-acetylcysteine. Silencing NLRP3 by a siRNA approach strikingly attenuated Aldo-induced podocyte apoptosis and nephrin protein downregulation in line with the blockade of caspase-1 and IL-18. In vivo, since day 5 of Aldo infusion, NLRP3 inflammasome activation and podocyte injury evidenced by nephrin reduction occurred concurrently. More importantly, immunofluorescence analysis showed a significant induction of NLRP3 in podocytes of glomeruli following Aldo infusion. In the mice with NLRP3 gene deletion, Aldo-induced downregulation of nephrin and podocin, podocyte foot processes, and albuminuria was remarkably improved, indicating an amelioration of podocyte injury. Finally, we observed a striking induction of NLRP3 in glomeruli and renal tubules in line with an enhanced urinary IL-18 output in nephrotic syndrome patients with minimal change disease or focal segmental glomerular sclerosis. Together, these results demonstrated an important role of NLRP3 inflammasome in mediating the podocyte injury induced by Aldo.

scholarly journals Emerging Role of the Inflammasome and Pyroptosis in Hypertension

2021 ◽  
Vol 22 (3) ◽  
pp. 1064
Author(s):  
Carmen De Miguel ◽  
Pablo Pelegrín ◽  
Alberto Baroja-Mazo ◽  
Santiago Cuevas
Keyword(s):  
Blood Pressure ◽  
Animal Models ◽  
Nlrp3 Inflammasome ◽  
Organ Damage ◽  
Subsequent Formation ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.

Sign in / Sign up

Export Citation Format

Share Document