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J Leukoc Biol. 2016 May;99(5):723-34. doi: 10.1189/jlb.3A0614-313RRR. Epub 2015 Nov 16.

Ion efflux and influenza infection trigger NLRP3 inflammasome signaling in human dendritic cells.

Author information

1
Department of Pathology, New York University School of Medicine, New York, New York, USA;
2
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;
3
Department of Microbiology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA;
4
Division of Hematology and Oncology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
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.

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.

KEYWORDS:

IL-1β; caspase-1; cell death; interferon; pyroptosis

PMID:
26574023
PMCID:
PMC4831479
DOI:
10.1189/jlb.3A0614-313RRR
[Indexed for MEDLINE]
Free PMC Article

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