Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17749-6
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Funding
- German Research Foundation [WA 2765/92, RO 4037/3-1, STA 1265/3-1, SFB 1052, 209933838, STR 477/14-2]
- European Fonds for Regional Development (EFRE)
- European Social Fonds
- CRC PolyTarget [1278 (316213987), C04/Z01]
- Medical Faculty, University Leipzig
- Projekt DEAL
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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-1 beta release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1 beta 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.
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