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

• DOI: 10.1038/s41467-020-17749-6
• Publication Date: 2020-08-25T10:04:04Z
• Authors: Elisabeth Jäger; Supriya Murthy; Caroline Schmidt; Magdalena Hahn; Sarah Strobel; Anna Peters; Claudia Stäubert; Pelin Sungur; Tom Venus; Mandy Geisler; Veselina Radusheva; Stefanie Raps; Kathrin Rothe; Roger Scholz; Sebastian Jung; Sylke Wagner; Matthias Pierer; Olga Seifert; Wenhan Chang; Irina Estrela-Lopis; Nora Raulien; Knut Krohn; Norbert Sträter; Stephanie Hoeppener; Torsten Schöneberg; Manuela Rossol; Ulf Wagner
• Keywords: Inflammatory arthritis; Pinocytosis; Calcium in biology

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