scholarly journals ER stress induces NLRP3 inflammasome activation and hepatocyte death

2015 ◽  
Vol 6 (9) ◽  
pp. e1879-e1879 ◽  
Author(s):  
C Lebeaupin ◽  
E Proics ◽  
C H D de Bieville ◽  
D Rousseau ◽  
S Bonnafous ◽  
...  
Keyword(s):  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Hepatocyte Death

scholarly journals Empagliflozin Alleviates Diabetic Renal Tubular Lipid Accumulation and NLRP3 Inflammasome Activation Through AGEs-RAGE Pathway

2021 ◽  
Author(s):  
Zheng Liu ◽  
Juan Chen ◽  
Lili Sun ◽  
Jianzhong Li ◽  
Hong Sun
Keyword(s):  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Lipid Accumulation ◽  
Cholesterol Metabolism ◽  
Basal Diet ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Renal Tubular

Abstract Background: Advanced glycation end products (AGEs) are pathogenic factors of renal tubular lipid accumulation and play a negative role in diabetic kidney disease (DKD). Glucose cotransporter (SGLT) 2 inhibition offers strong renoprotection in the progression of DKD. The aim of the current study was to investigate the effects of empagliflozin (EMPA, a potent and selective SGLT2 inhibitor) on AGEs-induced renal tubular lipid accumulation in both diabetic mice fed with a high-AGEs diet and AGEs-treated cultured human renal proximal tubular epithelial (HK-2) cells. Methods: In vivo, EMPA was used to treat db/db mice fed a high-AGEs diet or an AIN-76 basal diet. In an in vitro study, HK-2 cells were treated with AGEs-bovine serum albumin (BSA) and/or EMPA. Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) translocation was detected by confocal microscopy. Results: EMPA reduced tubular lipid droplets and intracellular cholesterol content, as well as the expression of proteins involved in the synthesis and absorption of cholesterol in the kidneys of basal diet-fed db/db mice, high-AGEs diet-fed db/db mice and AGEs-BSA-treated HK-2 cells. AGEs-BSA loading promoted the formation of SCAP-SREBP-2 complexes and enhanced the transport of the complexes to the Golgi, but these effects were markedly inhibited by EMPA in HK-2 cells. EMPA reduced renal inflammation both in basal diet-fed db/db mice and high-AGEs diet-fed db/db mice, and suppressed NLRP3 inflammasome activation in AGEs-BSA-treated HK-2 cells. In addition, EMPA reduced the serum AGEs level in vivo and inhibited renal tubular endoplasmic reticulum (ER) stress and receptor of AGEs (RAGE) expression both in vivo and in vitro. Conclusions: EMPA attenuated AGEs synthesis and inhibited the AGEs-RAGE signaling pathway, thereby suppressing ER stress and inhibiting abnormal cholesterol metabolism and release of inflammatory cytokines, thus alleviating renal tubular lipid accumulation and inflammation.

scholarly journals Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Liu Ye ◽  
Qi Zeng ◽  
Maoyao Ling ◽  
Riliang Ma ◽  
Haishao Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lung Injury ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Ventilator Induced Lung Injury ◽  
Nlrp3 Inflammasome Activation

RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

scholarly journals Gastrodin Alleviates Cognitive Dysfunction and Depressive-Like Behaviors by Inhibiting ER Stress and NLRP3 Inflammasome Activation in db/db Mice

2018 ◽  
Vol 19 (12) ◽  
pp. 3977 ◽  
Author(s):  
Tianyuan Ye ◽  
Xiangbao Meng ◽  
Ruiying Wang ◽  
Chenyang Zhang ◽  
Shuaibing He ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Er Stress ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Forced Swim Test ◽  
Inflammasome Activation ◽  
Diabetic Encephalopathy ◽  
Gas Treatment ◽  
Nlrp3 Inflammasome Activation

Patients with diabetes mellitus (DM) suffer more risks from diabetic encephalopathy such as cognitive dysfunction and depressive-like behaviors. Numerous studies show that ER (endoplasmic reticulum) stress and inflammation play important roles in the development of diabetic encephalopathy. Gastrodin (Gas), one major component of Gastrodia elata, is traditionally used in central nervous system disorders and is believed to possess anti-inflammatory, anti-apoptotic, and other neuroprotective effects. This present study aims to explore the protective effects of Gas on diabetic encephalopathy. Gas was administrated daily (70 and 140 mg/Kg) for 12 weeks. Meanwhile, the fasting blood glucose and body weight of db/db mice were measured every two weeks. After Gas treatment, the Morris water maze (MWM) test and novel object recognition (NOR) test were performed to assess the learning and memory functions of db/db mice, and the forced swim test was performed to evaluate depressive-like behaviors of db/db mice. Additionally, the expression of ER stress and Nucleotide binding and oligomerization domain-like (Nod) receptor family pyrin domain-containing 3 (NLRP3) inflammasome related proteins were evaluated by using Western blot. Our study suggested that Gas attenuated blood glucose levels and dyslipidemia of db/db mice. It has been shown that Gas could improve learning and memory function and depressive-like behaviors of db/db mice. Moreover, Gas inhibited ER stress and NLRP3 inflammasome activation in the hippocampus. Taken together, this study demonstrates that Gas attenuates the diabetic encephalopathy by inhibiting ER stress and NLRP3 inflammasome activation.

scholarly journals ER Stress Activates the NLRP3 Inflammasome: A Novel Mechanism of Atherosclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Xinnong Chen ◽  
Xiaochen Guo ◽  
Qihui Ge ◽  
Yixuan Zhao ◽  
Huaiyu Mu ◽  
...  
Keyword(s):  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Ros Generation ◽  
Macromolecular Complex ◽  
Inflammasome Activation ◽  
Cellular Processes ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
The Unfolded Protein Response

The endoplasmic reticulum (ER) is an important organelle that regulates several fundamental cellular processes, and ER dysfunction has implications for many intracellular events. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is an intracellularly produced macromolecular complex that can trigger pyroptosis and inflammation, and its activation is induced by a variety of signals. ER stress has been found to affect NLRP3 inflammasome activation through multiple effects including the unfolded protein response (UPR), calcium or lipid metabolism, and reactive oxygen species (ROS) generation. Intriguingly, the role of ER stress in inflammasome activation has not attracted a great deal of attention. In addition, increasing evidence highlights that both ER stress and NLRP3 inflammasome activation contribute to atherosclerosis (AS). AS is a common cardiovascular disease with complex pathogenesis, and the precise mechanisms behind its pathogenesis remain to be determined. Both ER stress and the NLRP3 inflammasome have emerged as critical individual contributors of AS, and owing to the multiple associations between these two events, we speculate that they contribute to the mechanisms of pathogenesis in AS. In this review, we aim to summarize the molecular mechanisms of ER stress, NLRP3 inflammasome activation, and the cross talk between these two pathways in AS in the hopes of providing new pharmacological targets for AS treatment.

scholarly journals Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia

2018 ◽  
Author(s):  
Yong Yang ◽  
Jianxin Li ◽  
Ting-Li Han ◽  
Xiaobo Zhou ◽  
Hongbo Qi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Nlrp3 Inflammasomes

AbstractPreeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been clarified. It has been reported that thioredoxin-interacting protein (TXNIP), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, plays a critical role in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1β (IL-1β) production in the placenta of patients with PE. The objective of the current study was to explore if TXNIP plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesised that ER stress would induce TXNIP production, which would bind with NLRP3 inflammasomes to activate IL-1β production. HTR8/SVneo cells were subjected to six hours hypoxia followed by six hours reoxygenation (H/R). These cells showed a higher protein level of NLRP3 and IL-1β, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with TXNIP siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. In addition, the outgrowth of explant with TXNIP lentivirus in H/R or Tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that TXNIP could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.

scholarly journals GDF11 alleviates neointimal hyperplasia in a rat model of artery injury by regulating endothelial NLRP3 inflammasome activation and rapid re-endothelialization

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Lei Li ◽  
Yan Gao ◽  
Zhenchuan Liu ◽  
Chenglai Dong ◽  
Wenli Wang ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Er Stress ◽  
Vascular Injury ◽  
Nlrp3 Inflammasome ◽  
Vascular Remodeling ◽  
Balloon Dilatation ◽  
Neointimal Hyperplasia ◽  
Inflammasome Activation ◽  
Neointima Formation ◽  
Nlrp3 Inflammasome Activation

Abstract Background Neointimal hyperplasia induced by interventional surgery can lead to progressive obliteration of the vascular lumen, which has become a major factor affecting prognosis. The rate of re-endothelialization is known to be inversely related to neointima formation. Growth differentiation factor 11 (GDF11) is a secreted protein with anti-inflammatory, antioxidant, and antiaging properties. Recent reports have indicated that GDF11 can improve vascular remodeling by maintaining the differentiated phenotypes of vascular smooth muscle cells. However, it is not known whether and how GDF11 promotes re-endothelialization in vascular injury. The present study was performed to clarify the influence of GDF11 on re-endothelialization after vascular injury. Methods An adult Sprague–Dawley rat model of common carotid artery balloon dilatation injury was surgically established. A recombinant adenovirus carrying GDF11 was delivered into the common carotid artery to overexpress GDF11. Vascular re-endothelialization and neointima formation were assessed in harvested carotid arteries through histomolecular analysis. CCK-8 analysis, LDH release and Western blotting were performed to investigate the effects of GDF11 on endothelial NLRP3 inflammasome activation and relevant signaling pathways in vitro. Results GDF11 significantly enhanced re-endothelialization and reduced neointima formation in rats with balloon-dilatation injury by suppressing the activation of the NLRP3 inflammasome. Administration of an endoplasmic reticulum stress (ER stress) inhibitor, 4PBA, attenuated endothelial NLRP3 inflammasome activation induced by lysophosphatidylcholine. In addition, upregulation of LOX-1 expression involved elevated ER stress and could result in endothelial NLRP3 inflammasome activation. Moreover, GDF11 significantly inhibited NLRP3 inflammasome-mediated endothelial cell pyroptosis by negatively regulating LOX-1-dependent ER stress. Conclusions We conclude that GDF11 improves re-endothelialization and can attenuate vascular remodeling by reducing endothelial NLRP3 inflammasome activation. These findings shed light on new treatment strategies to promote re-endothelialization based on GDF11 as a future target.

scholarly journals FXR Inhibits NLRP3 Inflammasome Activation by ER Stress

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Ayoung Kim ◽  
Chang Yeob Han ◽  
Hyun Soo Rho ◽  
Tae Hyun Kim ◽  
Sang Geon Kim
Keyword(s):  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation
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