Journal ArticleDOI
A role for mitochondria in NLRP3 inflammasome activation
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TLDR
It is shown that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome, and may explain the frequent association of mitochondrial damage with inflammatory diseases.Abstract:
An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.read more
Citations
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NF-κB signaling in inflammation
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Reactive Oxygen Species in Inflammation and Tissue Injury
TL;DR: The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.
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TL;DR: The complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response are discussed, and the similarities to another molecular signalling platform — the apoptosome — that monitors cellular health are highlighted.
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The NLRP3 inflammasome: molecular activation and regulation to therapeutics
TL;DR: The NLRP3 inflammasome mediates pro-inflammatory responses and pyroptotic cell death and how it is being targeted to treat inflammatory diseases is described.
References
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Journal ArticleDOI
Autophagy in the Pathogenesis of Disease
TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
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Gout-associated uric acid crystals activate the NALP3 inflammasome
TL;DR: It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.
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Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
Catherine Dostert,Virginie Pétrilli,Robin van Bruggen,Chad Steele,Brooke T. Mossman,Jürg Tschopp +5 more
TL;DR: It is shown that asbestos and silica are sensed by the Nalp3 inflammasome, whose subsequent activation leads to interleukin-1β secretion, and support its role as a major proinflammatory “danger” receptor in particulate matter–related pulmonary diseases.
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Calcium, ATP, and ROS: a mitochondrial love-hate triangle
TL;DR: A "two-hit" hypothesis is developed, in which Ca(2+) plus another pathological stimulus can bring about mitochondrial dysfunction, and the delicate balance between the positive and negative effects of Ca( 2+) and the signaling events that perturb this balance is highlighted.
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Thioredoxin-interacting protein links oxidative stress to inflammasome activation
TL;DR: The participation of TXNIP in the NLRP3 inflammasome activation may provide a mechanistic link to the observed involvement of IL-1β in the pathogenesis of type 2 diabetes.