Journal Article

Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis

Rossol, Manuela, Schmidt, Caroline, Pierer, Matthias, Hoeppener, Stephanie, Peters, Anna, Chang, Wenhan, Estrela-Lopis, Irina, Murthy, Supriya, Strobel, Sarah, Schöneberg, Torsten, Sungur, Pelin, Venus, Tom, Stäubert, Claudia, Krohn, Knut, Jäger, Elisabeth, Wagner, Sylke, Hahn, Magdalena, Jung, Sebastian, Radusheva, Veselina, Raulien, Nora, Geisler, Mandy, Wagner, Ulf, Sträter, Norbert, Rothe, Kathrin, Raps, Stefanie, Seifert, Olga, Scholz, Roger

2020

Overview

Increased extracellular Ca 2+ concentrations ([Ca 2+ ] ex ) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR). To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs). Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca 2+ ] ex . Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1β release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1β release in response to CaSR signaling. CaSR expression in these monocytes and local [Ca 2+ ] in afflicted joints are increased, probably contributing to this enhanced response. We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions. Inhibition of CaSR-mediated CPP uptake might be a therapeutic approach to treating RA. How extracellular calcium can trigger Nlrp3 inflammasome activation has been somewhat controversial and unclear. Here the authors show calciprotein particles are taken up by myeloid cells via calcium-sensing receptor-dependent macropinocytosis in response to high levels of extracellular Ca2+ and this pathway might be critical to inflammatory conditions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 631/250/256/2177 / 631/250/38 / 692/4023/808 / alpha-2-HS-Glycoprotein - metabolism / Animals / Arthritis / Arthritis, Rheumatoid - immunology / Calcification / Calcinosis / Calcium / Calcium (extracellular) / Calcium - metabolism / Calcium ions / Calcium phosphates / Calcium-sensing receptors / Cell activation / Cells, Cultured / Detection / Humanities and Social Sciences / Humans / IL-1β / Inflammasomes / Inflammasomes - metabolism / Inflammation / Interleukin-1beta - metabolism / Joint diseases / Mice / Monocytes / Monocytes - metabolism / multidisciplinary / Myeloid cells / NLR Family, Pyrin Domain-Containing 3 Protein - deficiency / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Phosphates - metabolism / Pinocytosis / Receptors / Receptors, Calcium-Sensing - deficiency / Receptors, Calcium-Sensing - metabolism / Rheumatoid arthritis / Science / Science (multidisciplinary) / Serum proteins / Signal Transduction / Signaling / THP-1 Cells