scholarly journals Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice

2018 ◽  
Vol 10 (465) ◽  
pp. eaah4066 ◽  
Author(s):  
Richard Gordon ◽  
Eduardo A. Albornoz ◽  
Daniel C. Christie ◽  
Monica R. Langley ◽  
Vinod Kumar ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Nlrp3 Inflammasome ◽  
Lewy Bodies ◽  
Adaptor Protein ◽  
Motor Deficits ◽  
Inflammasome Activation ◽  
Dopaminergic Neurodegeneration ◽  
Pyrin Domain ◽  
Chronic Neuroinflammation ◽  
Dopaminergic Degeneration

Parkinson’s disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein–rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein–mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.

scholarly journals Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1652
Author(s):  
Chinmaya Panda ◽  
Clara Voelz ◽  
Pardes Habib ◽  
Christian Mevissen ◽  
Thomas Pufe ◽  
...  
Keyword(s):  
Tau Protein ◽  
Nlrp3 Inflammasome ◽  
Time Dependent ◽  
Microglial Cells ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Progressive Dementia ◽  
Microglial Polarization ◽  
Protein Levels ◽  
Pyrin Domain

Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1β (IL1β) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.

scholarly journals MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration

2018 ◽  
Vol 26 (2) ◽  
pp. 213-228 ◽  
Author(s):  
Eunju Lee ◽  
Inhwa Hwang ◽  
Sangjun Park ◽  
Sujeong Hong ◽  
Boreum Hwang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Dopaminergic Neurodegeneration ◽  
Nlrp3 Inflammasome Activation

scholarly journals ASC filament formation serves as a signal amplification mechanism for inflammasomes

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Mathias S. Dick ◽  
Lorenzo Sborgi ◽  
Sebastian Rühl ◽  
Sebastian Hiller ◽  
Petr Broz
Keyword(s):  
Signal Amplification ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
Site Directed Mutagenesis ◽  
Cross Linking ◽  
Directed Mutagenesis ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Efficient Processing ◽  
Amplification Mechanism

Abstract A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASCPYD into filaments and cross-linking of these filaments by ASCCARD. ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASCPYD is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production.

scholarly journals Growth differentiation factor 11 ameliorates experimental colitis by inhibiting NLRP3 inflammasome activation

2018 ◽  
Vol 315 (6) ◽  
pp. G909-G920 ◽  
Author(s):  
Lanju Wang ◽  
Yaohui Wang ◽  
Zhenfeng Wang ◽  
Yu Qi ◽  
Beibei Zong ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Inflammasome Activation ◽  
Acute Colitis ◽  
Pyrin Domain ◽  
Differentiation Factor ◽  
Nlrp3 Inflammasome Activation ◽  
Receptor Family

Growth differentiation factor 11 (GDF11) has an anti-inflammatory effect in the mouse model of atherosclerosis and Alzheimer's disease, but how GDF11 regulates intestinal inflammation during ulcerative colitis (UC) is poorly defined. The Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome is closely associated with intestinal inflammation because of its ability to increase IL-1β secretion. Our aim is to determine whether GDF11 has an effect on attenuating experimental colitis in mice. In this study, using a dextran sodium sulfate (DSS)-induced acute colitis mouse model, we reported that GDF11 treatment attenuated loss of body weight, the severity of the disease activity index, shortening of the colon, and histological changes in the colon. GDF11 remarkably suppressed IL-1β secretion and NLRP3 inflammasome activation in colon samples and RAW 264.7 cells, such as the levels of NLRP3 and activated caspase-1. Furthermore, we found that GDF11 inhibited NLRP3 inflammasome activation by downregulating the Toll-like receptor 4/NF-κB p65 pathway and reactive oxygen species production via the typical Smad2/3 pathway. Thus, our research shows that GDF11 alleviates DSS-induced colitis by inhibiting NLRP3 inflammasome activation, providing some basis for its potential use in the treatment of UC. NEW & NOTEWORTHY Here, we identify a new role for growth differentiation factor 11 (GDF11), which ameliorates dextran sodium sulfate-induced acute colitis. Meanwhile, we discover a new phenomenon of GDF11 inhibiting IL-1β secretion and Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome activation. These findings reveal that GDF11 is a new potential candidate for the treatment of ulcerative colitis patients with a hyperactive NLRP3 inflammasome.

scholarly journals Genetic Deletion or Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Cardiac Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation

2019 ◽  
Vol 20 (14) ◽  
pp. 3502 ◽  
Author(s):  
Ahmed M. Darwesh ◽  
Hedieh Keshavarz-Bahaghighat ◽  
K. Lockhart Jamieson ◽  
John M. Seubert
Keyword(s):  
Nlrp3 Inflammasome ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Inflammasome Activation ◽  
Protective Effects ◽  
Isolated Hearts ◽  
Pyrin Domain ◽  
Cardioprotective Effects

Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response.

scholarly journals NLRP3 Inflammasome Is Involved in Calcium-Sensing Receptor-Induced Aortic Remodeling in SHRs

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Zhang ◽  
Siting Hong ◽  
Shuhan Qi ◽  
Wenxiu Liu ◽  
Xiaohui Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Activation Mechanism ◽  
Inflammasome Activation ◽  
Calcium Sensing Receptor ◽  
Pyrin Domain ◽  
Calcium Sensing ◽  
Nlrp3 Inflammasome Activation ◽  
Nucleotide Oligomerization ◽  
Aortic Remodeling ◽  
Receptor Family

Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.

scholarly journals The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1219 ◽  
Author(s):  
Yang Zhou ◽  
Zhizi Tong ◽  
Songhong Jiang ◽  
Wenyan Zheng ◽  
Jianjun Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Immune Defense ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Cholesterol Trafficking ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

scholarly journals Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia

2019 ◽  
Vol 216 (6) ◽  
pp. 1411-1430 ◽  
Author(s):  
Nikhil Panicker ◽  
Souvarish Sarkar ◽  
Dilshan S. Harischandra ◽  
Matthew Neal ◽  
Tae-In Kam ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Nuclear Translocation ◽  
Scavenger Receptor ◽  
Lewy Bodies ◽  
Inflammasome Activation ◽  
Signaling Mechanism ◽  
In Vivo Experiments ◽  
Fyn Kinase ◽  
Nlrp3 Inflammasome Activation

Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson’s disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent priming and activation of the microglial NLRP3 inflammasome. Fyn kinase regulates both of these processes; it mediates PKCδ-dependent NF-κB–p65 nuclear translocation, leading to inflammasome priming, and facilitates αSyn import into microglia, contributing to the generation of mitochondrial reactive oxygen species and consequently to inflammasome activation. In vivo experiments using A53T and viral-αSyn overexpression mouse models as well as human PD neuropathological results further confirm the role of Fyn in NLRP3 inflammasome activation. Collectively, our study identifies a novel Fyn-mediated signaling mechanism that amplifies neuroinflammation in PD.

scholarly journals Reversal of Endothelial Extracellular Vesicle-Induced Smooth Muscle Phenotype Transition by Hypercholesterolemia Stimulation: Role of NLRP3 Inflammasome Activation

2020 ◽  
Vol 8 ◽  
Author(s):  
Xinxu Yuan ◽  
Owais M. Bhat ◽  
Arun Samidurai ◽  
Anindita Das ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Nlrp3 Inflammasome ◽  
Vascular Endothelial Cells ◽  
Gene Knockout ◽  
Cell Communication ◽  
Extracellular Vesicle ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Phenotype Transition

Recent studies reported that vascular endothelial cells (ECs) secrete NLR family pyrin domain-containing 3 (NLRP3) inflammasome products such as interleukin-1β (IL-1β) via extracellular vesicles (EVs) under various pathological conditions. EVs represent one of the critical mechanisms mediating the cell-to-cell communication between ECs and vascular smooth muscle cells (VSMCs). However, whether or not the inflammasome-dependent EVs directly participate in the regulation of VSMC function remains unknown. In the present study, we found that in cultured carotid ECs, atherogenic stimulation by oxysterol 7-ketocholesterol (7-Ket) induced NLRP3 inflammasome formation and activation, reduced lysosome-multivesicular bodies (MVBs) fusion, and increased secretion of EVs that contain inflammasome product IL-1β. These EC-derived IL-1β-containing EVs promoted synthetic phenotype transition of co-cultured VSMCs, whereas EVs from unstimulated ECs have the opposite effects. Moreover, acid ceramidase (AC) deficiency or lysosome inhibition further exaggerated the 7-Ket-induced release of IL-1β-containing EVs in ECs. Using a Western diet (WD)-induced hypercholesterolemia mouse model, we found that endothelial-specific AC gene knockout mice (Asah1fl/fl/ECCre) exhibited augmented WD-induced EV secretion with IL-1β and more significantly decreased the interaction of MVBs with lysosomes in the carotid arterial wall compared to their wild-type littermates (WT/WT). The endothelial AC deficiency in Asah1fl/fl/ECCre mice also resulted in enhanced VSMC phenotype transition and accelerated neointima formation. Together, these results suggest that NLRP3 inflammasome-dependent IL-1β production during hypercholesterolemia promotes VSMC phenotype transition to synthetic status via EV machinery, which is controlled by lysosomal AC activity. Our findings provide novel mechanistic insights into understanding the pathogenic role of endothelial NLRP3 inflammasome in vascular injury through EV-mediated EC-to-VSMC regulation.

scholarly journals Inflammation in nonischemic heart disease: initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling

2019 ◽  
Vol 317 (5) ◽  
pp. H877-H890 ◽  
Author(s):  
Takeshi Suetomi ◽  
Shigeki Miyamoto ◽  
Joan Heller Brown
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Nlrp3 Inflammasome ◽  
Immune Cell ◽  
Cell Damage ◽  
Nuclear Factor Κb ◽  
Inflammasome Activation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Pyrin Domain ◽  
Cytokines And Chemokines

There is substantial evidence that chronic heart failure in humans and in animal models is associated with inflammation. Ischemic interventions such as myocardial infarction lead to necrotic cell death and release of damage associated molecular patterns, factors that signal cell damage and induce expression of proinflammatory chemokines and cytokines. It has recently become evident that nonischemic interventions are also associated with increases in inflammatory genes and immune cell accumulation in the heart and that these contribute to fibrosis and ventricular dysfunction. How proinflammatory responses are elicited in nonischemic heart disease which is not, at least initially, associated with cell death is a critical unanswered question. In this review we provide evidence supporting the hypothesis that cardiomyocytes are an initiating site of inflammatory gene expression in response to nonischemic stress. Furthermore we discuss the role of the multifunctional Ca2+/calmodulin-regulated kinase, CaMKIIδ, as a transducer of stress signals to nuclear factor-κB activation, expression of proinflammatory cytokines and chemokines, and priming and activation of the NOD-like pyrin domain-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. We summarize recent evidence that subsequent macrophage recruitment, fibrosis and contractile dysfunction induced by angiotensin II infusion or transverse aortic constriction are ameliorated by blockade of CaMKII, of monocyte chemoattractant protein-1/C-C chemokine receptor type 2 signaling, or of NLRP3 inflammasome activation.

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