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 and Ulf Wagner ()
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Manuela Rossol: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Matthias Pierer: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Nora Raulien: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Dagmar Quandt: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Undine Meusch: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Kathrin Rothe: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Kristin Schubert: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Torsten Schöneberg: Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, D-04103 Leipzig, Germany
Michael Schaefer: Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany
Ute Krügel: Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany
Sanela Smajilovic: Faculty of Health and Medical Sciences, University of Copenhagen, Fruebjergvej 3, 2100 Copenhagen, Denmark
Hans Bräuner-Osborne: Faculty of Health and Medical Sciences, University of Copenhagen, Fruebjergvej 3, 2100 Copenhagen, Denmark
Christoph Baerwald: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
Ulf Wagner: Rheumatology Unit, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany

Nature Communications, 2012, vol. 3, issue 1, 1-9

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2339

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