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Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux

The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (Nlrp3) inflammasome plays an important role in inflammation by controlling the maturation and secretion of the cytokines IL-1β and IL-18 in response to multiple stimuli including pore-forming toxins, particulate m...

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Main Authors: Franchi, Luigi (Author) , Eigenbrod, Tatjana (Author) , Muñoz-Planillo, Raúl (Author) , Ozkurede, Ulas (Author) , Kim, Yun-Gi (Author) , Chakrabarti, Arindam (Author) , Gale, Michael (Author) , Silverman, Robert H. (Author) , Colonna, Marco (Author) , Akira, Shizuo (Author) , Núñez, Gabriel (Author)
Format: Article (Journal)
Language:English
Published: 15 September 2014
In: The journal of immunology
Year: 2014, Volume: 193, Issue: 8, Pages: 4214-4222
ISSN:1550-6606
DOI:10.4049/jimmunol.1400582
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.4049/jimmunol.1400582
Verlag, lizenzpflichtig, Volltext: https://www.jimmunol.org/content/193/8/4214
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Author Notes:Luigi Franchi, Tatjana Eigenbrod, Raúl Muñoz-Planillo, Ulas Ozkurede, Yun-Gi Kim, Arindam Chakrabarti, Michael Gale, Robert H. Silverman, Marco Colonna, Shizuo Akira, and Gabriel Núñez
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Summary:The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (Nlrp3) inflammasome plays an important role in inflammation by controlling the maturation and secretion of the cytokines IL-1β and IL-18 in response to multiple stimuli including pore-forming toxins, particulate matter, and ATP. Although the pathways activated by the latter stimuli lead to a decrease in intracellular K+ concentration, which is required for inflammasome activation, the mechanism by which microbial RNA activates Nlrp3, remains poorly understood. In this study, we found that cytosolic poly(I:C), but not total RNA from healthy macrophages, macrophages undergoing pyroptosis, or mitochondrial RNA, induces caspase-1 activation and IL-1β release through the Nlrp3 inflammasome. Experiments with macrophages deficient in Tlr3, Myd88, or Trif, indicate that poly(I:C) induces Nlrp3 activation independently of TLR signaling. Further analyses revealed that the cytosolic sensors Rig-I and melanoma differentiation-associated gene 5 act redundantly via the common adaptor mitochondrial antiviral signaling (Mavs) to induce Nlrp3 activation in response to poly(I:C), but not ATP or nigericin. Mechanistically, Mavs triggered membrane permeabilization and K+ efflux independently of the inflammasome which were required for poly(I:C)-induced Nlrp3 activation. We conclude that poly (I:C) activates the inflammasome through an Mavs-dependent surveillance pathway that converges into a common K+ lowering step in the cytosol that is essential for the induction of Nlrp3 activation.
Item Description:Gesehen am 08.07.2020
Physical Description:Online Resource
ISSN:1550-6606
DOI:10.4049/jimmunol.1400582

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