Right place, right time: localisation and assembly of the NLRP3 inflammasome

Hamilton, Claire; Anand, Paras

doi:10.12688/f1000research.18557.1

Cited by 48 publications

(34 citation statements)

References 97 publications

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“…106 Though the precise cellular localization of NLRP3 is debatable, growing evidence indicates that NLRP3 is partly ER localized. [110][111][112][113] In line with cholesterol functions in other membranes, the authors speculated that ER cholesterol provides the necessary fluidity and or conformation for NLRP3 to sense activating stimuli. 106 Regardless, these findings suggest a critical role for cholesterol trafficking and ER cholesterol levels in NLRP3 inflammasome activation.…”

Section: Nlrp3 Infl Amma Some Is Reg Ul Ated By Np C1 and Endopl A mentioning

confidence: 98%

Lipids, inflammasomes, metabolism, and disease

Anand

2020

Immunological Reviews

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Inflammasomes are multi‐protein complexes that regulate the cleavage of cysteine protease caspase‐1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod‐like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.

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Section: Nlrp3 Infl Amma Some Is Reg Ul Ated By Np C1 and Endopl A mentioning

confidence: 98%

Lipids, inflammasomes, metabolism, and disease

Anand

2020

Immunological Reviews

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“…The first, often referred to as the priming step, involves engagement of a TLR and the induction of NF-κB signalling, which in turn leads to the transcriptional and translational upregulation of NLRP3 and pro-IL-1β. The second signal assembles and activates the NLRP3 inflammasome complex, leading to caspase-1 activation (17,40). We next studied the precise step at which ABCB1 is required for activation of the NLRP3 inflammasome by examining the expression of inflammasome components including NLRP3 and pro-IL-1β.…”

Section: Abcb1 Is Required For Tlr-dependent Priming and Activation Omentioning

confidence: 99%

NLRP3 inflammasome priming and activation are regulated by a novel phosphatidylinositol-dependent mechanism

Hamilton

Larrouy-Maumus

Anand

2020

Preprint

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Lipids are important in establishing cellular homeostasis by conducting varied functions including relay of extracellular signals. Imbalance in lipid homeostasis results in metabolic diseases, and is tightly connected to discrepancies in immune signalling. The phosphorylation status of the lipid second messenger phosphatidylinositol phosphates is implicated in key physiological functions and pathologies. By contrast, little is known as to how phosphatidylinositol (PI) lipid acyl chains contribute to cellular processes. Here, by employing a mass-spectrometry-based method, we show a role for PI acyl group chains in regulating NLRP3 inflammasome activation in cells lacking ABC transporter ABCB1. In response to canonical stimuli, Abcb1 -/cells revealed defective priming and activation of the NLRP3 inflammasome owing to blunted TLR-dependent signalling. Cellular lipidomics demonstrated that ABC transporter deficiency shifted the total PI balance such that Abcb1 -/cells exhibited reduced ratio of the short-chain to long-chain acyl chain lipids. Changes in PI acyl chain configuration accompanied diminished levels of ganglioside GM1, a marker of cholesterol-rich membrane microdomains, in deficient cells. Strikingly, this was not due to differences in the expression of enzymes that either synthesize PI or are involved in acyl chain remodelling. Our study thus suggests an important role for PI lipid chains in priming and activation of the NLRP3 inflammasome thereby highlighting the metabolic regulation of immune responses.

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“…To exert its functions, the NLRP3 inflammasome requires to be activated. The NLRP3 inflammasome can be triggered by an array of stimuli, including ATP, potassium efflux, heme, urate, and reactive oxygen species (ROS) [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy: implication in neuroinflammation in hypoxemic adult rats

Ding

Liu

et al. 2019

Preprint

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Background: Hypoxemia is a typical symptom of acute respiratory distress syndrome (ARDS). Ventilations are always needed for correcting hypoxemia. To avoid pulmonary morbidity, low tidal volume ventilation is often applied. The ventilation strategy will certainly result in hypercapnia. Our previous study found that hypercapnia could induce IL-1β overproduction in hypoxia-activated microglia. However, the underlying mechanism has remained unclear. This study aimed to explore whether hypercapnia would promote microglial pyroptosis via inhibiting mitophagy in adult rats with hypoxemia. Methods: Cerebral oxygen extraction ratio (CERO2), partial pressure of brain tissue oxygen (PbtO2), and reactive oxygen species (ROS) production in brain tissue in a rat model of hypercapnia/hypoxemia were evaluated. Along with this, the oxygen consumption rate (OCR) and ROS production of BV-2 microglial cells were evaluated after 15% CO2/0.2% O2 treatment. Mitophagy was observed using transmission electron microscopy (TEM). The protein expression level of LC3-II/I, p62, caspase-1, gasdermin D-N domains (GSDMD-N), IL-1β and IL-18 in microglial cells were detected before and after application of a ROS scavenger in vivo and in vitro. Results: PbtO2 level was elevated by hypercapnia in the hypoxemic rats in the first 1.5 h, but it was significantly decreased 2 h after ventilation. This was further evident by the increased levels of CERO2 at 3 h after ventilation. Besides, a high concentration of CO2 treatment could increase the levels of OCR in hypoxic BV-2 microglial cells in vitro. Expression levels of LC3-II were reduced, while those of p62 were increased by hypercapnia in the hypoxic hippocampus and BV-2 microglia. Autophagosomes could be seen in hypoxia treated microglial cells under TEM, while those were rarely observed in hypercapnia + hypoxia treated microglia. Hypercapnia markedly increased the production of ROS and the expression of caspase-1, GSDMD-N, IL-1β, and IL-18 in hypoxia-activated microglia both in vivo and in vitro. Pharmacological scavenging ROS inhibited microglial pyroptosis and expression of IL-1β and IL-18.Conclusion: Hypercapnia-induced mitophagy inhibition may promote pyroptosis and enhance IL-1β and IL-18 release in hypoxia-activated microglia.

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Right place, right time: localisation and assembly of the NLRP3 inflammasome

Cited by 48 publications

References 97 publications

Lipids, inflammasomes, metabolism, and disease

Lipids, inflammasomes, metabolism, and disease

NLRP3 inflammasome priming and activation are regulated by a novel phosphatidylinositol-dependent mechanism

Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy: implication in neuroinflammation in hypoxemic adult rats

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