Extracellular Ca2+ is a Danger Signal Activating the NLRP3 Inflammasome Through G Protein-coupled Calcium Sensing Receptors

Overview

Journal Nat Commun

Specialty Biology

Date 2012 Dec 29

PMID 23271661

Citations 206

Authors

Manuela Rossol

Matthias Pierer

Nora Raulien

Dagmar Quandt

Undine Meusch

Kathrin Rothe

Kristin Schubert

Torsten Schoneberg

Michael Schaefer

Ute Krugel

Sanela Smajilovic

Hans Brauner-Osborne

Christoph Baerwald

Ulf Wagner

Affiliations

Soon will be listed here.

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.

Citing Articles

Podocyte specific knockout of the natriuretic peptide clearance receptor is podocyte protective in focal segmental glomerulosclerosis.

Wang L, Tang Y, Buckley A, Spurney R PLoS One. 2025; 20(3):e0319424.

PMID: 40063586 PMC: 11892885. DOI: 10.1371/journal.pone.0319424.

Mental Health Disorders Due to Gut Microbiome Alteration and NLRP3 Inflammasome Activation After Spinal Cord Injury: Molecular Mechanisms, Promising Treatments, and Aids from Artificial Intelligence.

Kalaga P, Ray S Brain Sci. 2025; 15(2).

PMID: 40002529 PMC: 11852823. DOI: 10.3390/brainsci15020197.

Understanding the Role of NLRP3 Inflammasome in Acute Pancreatitis.

Papantoniou K, Aggeletopoulou I, Michailides C, Pastras P, Triantos C Biology (Basel). 2024; 13(11).

PMID: 39596901 PMC: 11592098. DOI: 10.3390/biology13110945.

Staphylococcus epidermidis alters macrophage polarization and phagocytic uptake by extracellular DNA release in vitro.

Weisselberg S, Both A, Failla A, Huang J, Linder S, Ohnezeit D NPJ Biofilms Microbiomes. 2024; 10(1):131.

PMID: 39567551 PMC: 11579364. DOI: 10.1038/s41522-024-00604-7.

Potential Roles of IP Receptors and Calcium in Programmed Cell Death and Implications in Cardiovascular Diseases.

Piamsiri C, Fefelova N, Pamarthi S, Gwathmey J, Chattipakorn S, Chattipakorn N Biomolecules. 2024; 14(10).

PMID: 39456267 PMC: 11506173. DOI: 10.3390/biom14101334.

References

Christiansen B, Hansen K, Wellendorph P, Brauner-Osborne H . Pharmacological characterization of mouse GPRC6A, an L-alpha-amino-acid receptor modulated by divalent cations. Br J Pharmacol. 2007; 150(6):798-807. PMC: 2013871. DOI: 10.1038/sj.bjp.0707121. View

SOLLE M, Labasi J, Perregaux D, Stam E, Petrushova N, Koller B . Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem. 2000; 276(1):125-32. DOI: 10.1074/jbc.M006781200. View

Piccini A, Carta S, Tassi S, Lasiglie D, Fossati G, Rubartelli A . ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way. Proc Natl Acad Sci U S A. 2008; 105(23):8067-72. PMC: 2430360. DOI: 10.1073/pnas.0709684105. View

Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer A . Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012; 109(28):11282-7. PMC: 3396518. DOI: 10.1073/pnas.1117765109. View

Rossol M, Meusch U, Pierer M, Kaltenhauser S, Hantzschel H, Hauschildt S . Interaction between transmembrane TNF and TNFR1/2 mediates the activation of monocytes by contact with T cells. J Immunol. 2007; 179(6):4239-48. DOI: 10.4049/jimmunol.179.6.4239. View

Morris C . Carrageenan-induced paw edema in the rat and mouse. Methods Mol Biol. 2003; 225:115-21. DOI: 10.1385/1-59259-374-7:115. View

Gross O, Yazdi A, Thomas C, Masin M, Heinz L, Guarda G . Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity. 2012; 36(3):388-400. DOI: 10.1016/j.immuni.2012.01.018. View

Duewell P, Kono H, Rayner K, Sirois C, Vladimer G, Bauernfeind F . NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464(7293):1357-61. PMC: 2946640. DOI: 10.1038/nature08938. View

Larsen C, Faulenbach M, Vaag A, Volund A, Ehses J, Seifert B . Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007; 356(15):1517-26. DOI: 10.1056/NEJMoa065213. View

10.

Hofer A, Curci S, Doble M, Brown E, Soybel D . Intercellular communication mediated by the extracellular calcium-sensing receptor. Nat Cell Biol. 2000; 2(7):392-8. DOI: 10.1038/35017020. View

11.

Gabay C, Lamacchia C, Palmer G . IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010; 6(4):232-41. DOI: 10.1038/nrrheum.2010.4. View

12.

Faure H, Gorojankina T, Rice N, Dauban P, Dodd R, Brauner-Osborne H . Molecular determinants of non-competitive antagonist binding to the mouse GPRC6A receptor. Cell Calcium. 2009; 46(5-6):323-32. DOI: 10.1016/j.ceca.2009.09.004. View

13.

Masters S, Dunne A, Subramanian S, Hull R, Tannahill G, Sharp F . Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol. 2010; 11(10):897-904. PMC: 3103663. DOI: 10.1038/ni.1935. View

14.

KASLICK R, Chasens A, MANDEL I, Weinstein D, Waldman R, Pluhar T . Quantitative analysis of sodium, potassium and calcium in gingival fluid from gingiva in varying degrees of inflammation. J Periodontol. 1970; 41(2):93-7. DOI: 10.1902/jop.1970.41.2.93. View

15.

Boraschi D, Dinarello C . IL-18 in autoimmunity: review. Eur Cytokine Netw. 2007; 17(4):224-52. View

16.

Chen G, Nunez G . Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10(12):826-37. PMC: 3114424. DOI: 10.1038/nri2873. View

17.

Martinon F, Burns K, Tschopp J . The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002; 10(2):417-26. DOI: 10.1016/s1097-2765(02)00599-3. View

18.

Wellendorph P, Johansen L, Jensen A, Casanova E, Gassmann M, Deprez P . No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions. J Mol Endocrinol. 2008; 42(3):215-23. DOI: 10.1677/JME-08-0149. View

19.

Wolff T, Leipziger J, Fischer K, Klar B, Nitschke R, Greger R . Evidence for agonist-induced export of intracellular Ca2+ in epithelial cells. Pflugers Arch. 1993; 424(5-6):423-30. DOI: 10.1007/BF00374904. View

20.

Korff S, Riechert N, Schoensiegel F, Weichenhan D, Autschbach F, Katus H . Calcification of myocardial necrosis is common in mice. Virchows Arch. 2005; 448(5):630-8. DOI: 10.1007/s00428-005-0071-7. View