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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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Autophagy / drug effects
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CARD Signaling Adaptor Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Endoplasmic Reticulum / metabolism
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Humans
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Immunity, Innate
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Inflammasomes / drug effects
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Inflammasomes / metabolism*
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Inflammation / metabolism
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Inflammation / pathology
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Interleukin-1beta / metabolism
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Macrophages / cytology
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitochondria / pathology
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NLR Family, Pyrin Domain-Containing 3 Protein
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Reactive Oxygen Species / metabolism
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Thioredoxins / genetics
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Thioredoxins / metabolism
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Voltage-Dependent Anion Channels / metabolism
Substances
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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Inflammasomes
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Interleukin-1beta
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nlrp3 protein, mouse
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PYCARD protein, human
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Pycard protein, mouse
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Reactive Oxygen Species
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TXNIP protein, human
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Txnip protein, mouse
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Voltage-Dependent Anion Channels
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Thioredoxins