title: Ion efflux and influenza infection trigger NLRP3 inflammasome signaling in human dendritic cells.
abstract: The nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, a multiprotein complex, is an essential intracellular mediator of antiviral immunity. In murine dendritic cells, this complex responds to a wide array of signals, including ion efflux and influenza A virus infection, to activate caspase-1-mediated proteolysis of IL-1β and IL-18 into biologically active cytokines. However, the presence and function of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells, in response to various triggers, including viral infection, has not been defined clearly. Here, we delineate the contribution of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome to the secretion of IL-1β, IL-18, and IL-1α by human dendritic cells (monocyte-derived and primary conventional dendritic cells). Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells by various synthetic activators resulted in the secretion of bioactive IL-1β, IL-18, and IL-1α and induction of pyroptotic cell death. Cellular IL-1β release depended on potassium efflux and the activity of proteins nucleotide-binding oligomerization domain-like receptor protein 3 and caspase-1. Likewise, influenza A virus infection of dendritic cells resulted in priming and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and secretion of IL-1β and IL-18 in an M2- and nucleotide-binding oligomerization domain-like receptor protein 3-dependent manner. The magnitude of priming by influenza A virus varied among different strains and inversely corresponded to type I IFN production. To our knowledge, this is the first report describing the existence and function of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells and the ability of influenza A virus to prime and activate this pathway in human dendritic cells, with important implications for antiviral immunity and pathogenesis.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA;
authors.forename: Melissa Victoria
authors.initials: MV
authors.lastname: Fernandez
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Miller
authors.affiliation: Department of Microbiology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA;
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Division of Hematology and Oncology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Gopal
authors.affiliation: Division of Hematology and Oncology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Greenbaum
authors.affiliation: Division of Hematology and Oncology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA nina.bhardwaj@mssm.edu.
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D000547:Amantadine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D009980:Influenza A virus / Q000502:physiology*; D007372:Interferons / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D007477:Ions / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D012299:Rimantadine / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007093:Imidazoles; D058847:Inflammasomes; D007375:Interleukin-1; D007477:Ions; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D051193:Toll-Like Receptors; D012299:Rimantadine; D007372:Interferons; D000547:Amantadine; D020170:Caspase 1; C402365:resiquimod
keywords: IL-1β; caspase-1; cell death; interferon; pyroptosis