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

Luigi Franchi, Tatjana Eigenbrod, Raúl Muñoz-Planillo, Ulas Ozkurede, Yun Gi Kim, Arindam Chakrabarti, Michael Gale, Robert H. Silverman, Marco Colonna, Shizuo Akira, Gabriel Núñez

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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.

Original languageEnglish
Pages (from-to)4214-4222
Number of pages9
JournalJournal of Immunology
Volume193
Issue number8
DOIs
Publication statusPublished - 2014 Oct 15

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Franchi, L., Eigenbrod, T., Muñoz-Planillo, R., Ozkurede, U., Kim, Y. G., Chakrabarti, A., Gale, M., Silverman, R. H., Colonna, M., Akira, S., & Núñez, G. (2014). Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. Journal of Immunology, 193(8), 4214-4222. https://doi.org/10.4049/jimmunol.1400582