Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and caspase-1-mediated interleukin-1β secretion

Liao, Pei‐Chun; Chao, Louis Kuoping; Chou, Ju-Ching; Dong, Wei-Chih; Lin, Chien-Nan; Lin, Chia-Yang; Chen, Ann; Ka, Shuk‐Man; Ho, Chyi-Chen; Hua, Kuo-Feng

doi:10.1007/s00011-012-0555-2

Cited by 90 publications

(91 citation statements)

References 38 publications

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“…S100A8/S100A9 heterodimers activate both NF-kB and NLRP3 inflammasome assembly via a NOX/ROS-dependent mechanism. 23,[44][45][46] Intracellularly, S100A8/9 heterodimers serve as a scaffold for the membrane assembly and activation of the NOX complex, 47,48 which generates ROS via transfer of electrons across membranes to generate superoxide. 49 As also shown here, NOX regulates both priming and activation of NLRP3 inflammasomes, including the activation of caspase-1 and IL-1b secretion.…”

Section: Discussionmentioning

confidence: 99%

“…49 As also shown here, NOX regulates both priming and activation of NLRP3 inflammasomes, including the activation of caspase-1 and IL-1b secretion. 44 Moreover, transcription and nuclear localization of b-catenin are redox and NOX1 dependent. 50,51 Although MDSCs are a key paracrine source of S100A9 in the MDS BM microenvironment, 11 we show here that MDS HSPCs also express high intracellular S100A9 across lineages, suggesting that inflammasome activation may be sustained by intracrine DAMP stimulation and, upon cytolysis, reinforce paracrine TLR4 activation and BM MDSC expansion.…”

Section: Discussionmentioning

confidence: 99%

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The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

297

350

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

297

350

View full text Add to dashboard Cite

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“…36,37 Several laboratories, including ours, have shown that QDs can induce excessive ROS formation 38À41 and activation of microglia, 42 and the release of cytokines including interleukin-1β (IL-1β). 43,44 However, these earlier studies did not provide experimental evidence for a mechanistic link between the activation of microglia, lysosomal status, and activation pattern of caspase-1 together with the subsequent release of IL-1β. In the current study, we describe a ratiometric QD-based nanosensor for caspase-1 activity detection.…”

Section: Resultsmentioning

confidence: 93%

“…3,61 In LPS and LPSÀQD treated microglia, we found significantly increased levels of IL-1β as determined by ELISA assays ( Figure 4A). 43 The viability of the cells exposed to LPS and/or LPSÀQD (100 ng/mL and 10 μg/mL) in the presence of serum was within 10% from the control. To determine the activity of caspase-1 which leads to the conversion of pro-IL-1β to IL-1β, we developed and employed a novel nanosensor.…”

Section: Articlementioning

confidence: 87%

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Caspase-1 Activity in Microglia Stimulated by Pro-Inflammagen Nanocrystals

Moquin¹,

Hutter

Choi

et al. 2013

ACS Nano

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These authors share equal first authorship.A n acute inflammatory response to an insult is largely a protective cellular response. An unopposed acute inflammatory process persists, leading to the characteristic chronic inflammation. Commonly, the sequel would be a deterioration of physiological function. An early intervention is therefore important to reduce or eliminate this undesirable consequence. To this end, several biomarkers of inflammation have been measured and tested; these biomarkers are mainly the products of enzymatic reactions. Caspase-1 is one of the most prominent of the enzymes involved in inflammation. 1 Inflammation can be induced by numerous exogenous agents, including airborne particles, biological aggregates, nanocrystals (quantum dots (QDs)) and lipopolysaccharides (LPS). 2 These inflammagens are recognized by macrophages and microglia and some of them bind to cell surface receptors such as Toll-like receptors (TLR). In particular, endotoxins, including LPS, bind TLR-4 and trigger receptor dimerization at the plasma membrane, which, in turn, activate signal transduction cascades to induce inflammation. 1 TLR-4 activation initiates both genomic and nongenomic inflammatory responses (i) by activating the transcription factor NF-κB, which translocates to the nucleus and induces the expression of pro-inflammatory cytokines (e.g., pro-interleukins), and (ii) by internalizing the bound endotoxin stimuli, fusing with lysosomes and triggering the formation of inflammasomes ( Figure 1A). Nod-like receptor protein-3 (NLRP-3) inflammasome 3À6 is one of the most wellstudied inflammasomes and contains the precursor pro-caspase-1, which is cleaved following inflammatory stimuli and releases its active form, caspase-1. 7 Caspase-1 is a cysteine protease which converts * Address correspondence to dusica.maysinger@mcgill.ca.Received for review January 14, 2013 and accepted October 9, 2013. Published online 10.1021/nn404473gABSTRACT Although caspase-1 is a key participant in inflammation, there is no sensitive assay to measure its enzymatic activity in real time in cells or animals. Here we describe a nanosensor for caspase-1 ratiometric measurements, consisting of a rhodamine-labeled, caspase-1 cleavable peptide linked to quantum dots (QDs). Microglia cells were stimulated by lipopolysaccharide (LPS) and by hybrid nanoparticles LPSÀQDs. These stimuli activated caspase-1 in microglia monolayers and in the mouse brain, while a selected caspase inhibitor markedly reduced it. LPSÀQDs entered into the lysosomal compartment and led to an enlargement of these cellular organelles in the exposed microglia. Both lysosomal swelling and mitochondrial impairment contributed to caspase-1 activation and to the consequent interleukin-1β release. The results from these studies highlight how the unique properties of QDs can be used to create versatile biotools in the study of inflammation in real time in vivo.

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Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

Mangali

Bhat

Udumula

et al. 2018

J of Cellular Biochemistry

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Background and Purpose: Double-stranded RNA-dependent protein kinase (PKR) is a critical regulator of apoptosis, oxidative stress, and inflammation under hyperlipidemic and insulin resistance conditions. Saturated free fatty acids, such as palmitic acid (PA), are known inducers of apoptosis in numerous cell types. However, the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of PA on cultured rat H9C2 cardiac myocytes cells and to investigate the PKR mediated harmful effects of PA in vitro in cultured cardiomyocytes.Experimental Approach: PKR expression was determined by immunofluorescence and immunoblotting. Oxidative stress and apoptosis were determined by flow cytometry and assay kits. The expression of different gene markers of apoptosis, oxidative stress, and inflammation were measured by Western blot analysis and reverse transcription polymerase chain reaction.Key Results: PKR expression, reactive oxygen species levels as well as apoptosis were increased in PA-treated cultured H9C2 cardiomyocytes. The harmful effects of PA were attenuated by a selective PKR inhibitor, C16.Moreover, we observed that upregulation of c-Jun N-terminal kinase (JNK), nuclear factor-kB (NF-kB) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) pathways is associated with increased expression of interleukin 6 and tumor necrosis factor-α in PA-treated cardiomyocytes and attenuation by a selective PKR inhibitor.Conclusion and Implications: Our study reports, for the first time, that PKRmediated harmful effects of PA in cultured cardiomyocytes via activation of

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Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and caspase-1-mediated interleukin-1β secretion

Abstract: These results demonstrate that ROS regulates not only the priming stage, but also the activation stage, of NLRP3 inflammasome activation in LPS + ATP-activated macrophages.

Cited by 90 publications

References 38 publications

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Caspase-1 Activity in Microglia Stimulated by Pro-Inflammagen Nanocrystals

Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

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