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/Ca(2+) 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.
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rossol
authors.forename: Matthias
authors.initials: M
authors.lastname: Pierer
authors.forename: Nora
authors.initials: N
authors.lastname: Raulien
authors.forename: Dagmar
authors.initials: D
authors.lastname: Quandt
authors.forename: Undine
authors.initials: U
authors.lastname: Meusch
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rothe
authors.forename: Kristin
authors.initials: K
authors.lastname: Schubert
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.forename: Ute
authors.initials: U
authors.lastname: Krügel
authors.forename: Sanela
authors.initials: S
authors.lastname: Smajilovic
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Christoph
authors.initials: C
authors.lastname: Baerwald
authors.forename: Ulf
authors.initials: U
authors.lastname: Wagner
mesh_terms: D000818:Animals; D002118:Calcium / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; C488584:GPRC6A protein, human; C515750:GPRC6A protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D002118:Calcium