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

Abstract

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.

• Authors: Luigi Franchi, Tatjana Eigenbrod, Raúl Muñoz-Planillo, Ulas Ozkurede, Yun-Gi Kim, Chakrabarti Arindam, Michael Gale Jr, Robert H Silverman, Marco Colonna, Shizuo Akira, Gabriel Núñez
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 8 Pg. 4214-4222 (Oct 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25225670 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport
• Carrier Proteins
• IL1B protein, mouse
• IPS-1 protein, mouse
• Interleukin-18
• Interleukin-1beta
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• RNA, Bacterial
• RNA, Double-Stranded
• RNA, Viral
• TICAM-1 protein, mouse
• TLR3 protein, mouse
• Toll-Like Receptor 3
• Caspase 1
• Ddx58 protein, mouse
• Ifih1 protein, mouse
• DEAD Box Protein 58
• DEAD-box RNA Helicases
• Interferon-Induced Helicase, IFIH1
• Poly I-C
• Potassium

Topics

• Adaptor Proteins, Signal Transducing (immunology)
• Adaptor Proteins, Vesicular Transport (genetics)
• Animals
• Carrier Proteins (immunology)
• Caspase 1 (immunology)
• Cytosol
• DEAD Box Protein 58
• DEAD-box RNA Helicases (immunology)
• Inflammation (immunology)
• Interferon-Induced Helicase, IFIH1
• Interleukin-18 (biosynthesis, metabolism)
• Interleukin-1beta (biosynthesis, metabolism)
• Ion Transport
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Poly I-C (immunology)
• Potassium (metabolism)
• RNA, Bacterial (immunology)
• RNA, Double-Stranded (immunology)
• RNA, Viral (immunology)
• Signal Transduction (immunology)
• Toll-Like Receptor 3 (genetics)