title: 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.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.|Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Eigenbrod
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Raúl
authors.initials: R
authors.lastname: Muñoz-Planillo
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Ulas
authors.initials: U
authors.lastname: Ozkurede
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Yun-Gi
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Chakrabarti
authors.initials: C
authors.lastname: Arindam
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D003600:Cytosol; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D000072640:Interferon-Induced Helicase, IFIH1; D020382:Interleukin-18 / Q000096:biosynthesis / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D017136:Ion Transport; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011070:Poly I-C / Q000276:immunology; D011188:Potassium / Q000378:metabolism*; D012329:RNA, Bacterial / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D020170:Caspase 1; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020382:Interleukin-18; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011070:Poly I-C; D011188:Potassium; D012329:RNA, Bacterial; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051196:Toll-Like Receptor 3; C587672:IL1B protein, mouse; C512612:MAVS protein, mouse; C507780:Myd88 protein, mouse; C492716:Nlrp3 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse