Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors
Top Cited Papers
Open Access
- 1 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 3 (1), 1329
- https://doi.org/10.1038/ncomms2339
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.This publication has 30 references indexed in Scilit:
- Critical role for calcium mobilization in activation of the NLRP3 inflammasomeProceedings of the National Academy of Sciences of the United States of America, 2012
- Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1Immunity, 2012
- Sterile inflammation: sensing and reacting to damageNature Reviews Immunology, 2010
- Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetesNature Immunology, 2010
- NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystalsNature, 2010
- Mechanisms of multimodal sensing by extracellular Ca2+‐sensing receptors: a domain‐based survey of requirements for binding and signallingBritish Journal of Pharmacology, 2010
- No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditionsJournal of Molecular Endocrinology, 2008
- ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine wayProceedings of the National Academy of Sciences of the United States of America, 2008
- Pharmacological characterization of mouse GPRC6A, an L‐α‐amino‐acid receptor modulated by divalent cationsBritish Journal of Pharmacology, 2007
- Quantitative Analysis of Sodium, Potassium and Calcium in Gingival Fluid from Gingiva in Varying Degrees of InflammationThe Journal of Periodontology, 1970