Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors

Manuela Rossol, Matthias Pierer, Nora Raulien, Dagmar Quandt, Undine Meusch, Kathrin Rothe, Kristin Schubert, Torsten Schöneberg, Michael Schaefer, Ute Krügel, Sanela Smajilovic, Hans Bräuner-Osborne, Christoph Baerwald, Ulf Wagner

    246 Citations (Scopus)

    Abstract

    Activation of the NLRP3 inflammasome enables monocytes and macrophages to release high levels of interleukin-1β during inflammatory responses. Concentrations of extracellular calcium can increase at sites of infection, inflammation or cell activation. Here we show that increased extracellular calcium activates the NLRP3 inflammasome via stimulation of G protein-coupled calcium sensing receptors. Activation is mediated by signalling through the calcium-sensing receptor and GPRC6A via the phosphatidyl inositol/Ca2 pathway. The resulting increase in the intracellular calcium concentration triggers inflammasome assembly and Caspase-1 activation. We identified necrotic cells as one source for excess extracellular calcium triggering this activation. In vivo, increased calcium concentrations can amplify the inflammatory response in the mouse model of carrageenan-induced footpad swelling, and this effect was inhibited in GPRC6A -/- mice. Our results demonstrate that G-protein-coupled receptors can activate the inflammasome, and indicate that increased extracellular calcium has a role as a danger signal and amplifier of inflammation.

    Original languageEnglish
    JournalNature Communications
    Volume3
    Pages (from-to)1329
    ISSN2041-1723
    DOIs
    Publication statusPublished - 2012

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