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

doi:10.1038/ncomms2339

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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature Communications
Vol/bind	3
Sider (fra-til)	1329
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms2339
Status	Udgivet - 2012

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10.1038/ncomms2339

Citationsformater

Rossol, M., Pierer, M., Raulien, N., Quandt, D., Meusch, U., Rothe, K., Schubert, K., Schöneberg, T., Schaefer, M., Krügel, U., Smajilovic, S., Bräuner-Osborne, H., Baerwald, C., & Wagner, U. (2012). Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nature Communications, 3, 1329. https://doi.org/10.1038/ncomms2339

Rossol, M, Pierer, M, Raulien, N, Quandt, D, Meusch, U, Rothe, K, Schubert, K, Schöneberg, T, Schaefer, M, Krügel, U, Smajilovic, S, Bräuner-Osborne, H, Baerwald, C & Wagner, U 2012, 'Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors', Nature Communications, bind 3, s. 1329. https://doi.org/10.1038/ncomms2339

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

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.",

author = "Manuela Rossol and Matthias Pierer and Nora Raulien and Dagmar Quandt and Undine Meusch and Kathrin Rothe and Kristin Schubert and Torsten Sch{\"o}neberg and Michael Schaefer and Ute Kr{\"u}gel and Sanela Smajilovic and Hans Br{\"a}uner-Osborne and Christoph Baerwald and Ulf Wagner",

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T1 - Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors

AU - Rossol, Manuela

AU - Pierer, Matthias

AU - Raulien, Nora

AU - Quandt, Dagmar

AU - Meusch, Undine

AU - Rothe, Kathrin

AU - Schubert, Kristin

AU - Schöneberg, Torsten

AU - Schaefer, Michael

AU - Krügel, Ute

AU - Smajilovic, Sanela

AU - Bräuner-Osborne, Hans

AU - Baerwald, Christoph

AU - Wagner, Ulf

N1 - Article number: 1329

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms2339

DO - 10.1038/ncomms2339

M3 - Journal article

C2 - 23271661

SN - 2041-1723

VL - 3

SP - 1329

JO - Nature Communications

JF - Nature Communications

ER -

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

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