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

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 () and Ulf Wagner ()
Additional contact information
Elisabeth Jäger: Leipzig University
Supriya Murthy: Leipzig University
Caroline Schmidt: Leipzig University
Magdalena Hahn: Leipzig University
Sarah Strobel: Leipzig University
Anna Peters: Leipzig University
Claudia Stäubert: Leipzig University
Pelin Sungur: Friedrich-Schiller-University Jena
Tom Venus: Leipzig University
Mandy Geisler: Leipzig University
Veselina Radusheva: Leipzig University
Stefanie Raps: Leipzig University
Kathrin Rothe: Leipzig University
Roger Scholz: Leipzig University
Sebastian Jung: Leipzig University
Sylke Wagner: Leipzig University
Matthias Pierer: Leipzig University
Olga Seifert: Leipzig University
Wenhan Chang: UCSF Department of Veterans Affairs Medical Center
Irina Estrela-Lopis: Leipzig University
Nora Raulien: Leipzig University
Knut Krohn: DNA Core Unit Leipzig
Norbert Sträter: Leipzig University
Stephanie Hoeppener: Friedrich-Schiller-University Jena
Torsten Schöneberg: Leipzig University
Manuela Rossol: Leipzig University
Ulf Wagner: Leipzig University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Increased extracellular Ca2+ concentrations ([Ca2+]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 [Ca2+]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 [Ca2+] 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-17749-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17749-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-17749-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().