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Murthy, S.* ; Karkossa, I.* ; Schmidt, C.* ; Hoffmann, A. ; Hagemann, T. ; Rothe, K.* ; Seifert, O.* ; Anderegg, U.* ; von Bergen, M.* ; Schubert, K.* ; Rossol, M.*

Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages.

Cell Death Dis. 13:53 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The danger signal extracellular calcium is pathophysiologically increased in the synovial fluid of patients with rheumatoid arthritis (RA). Calcium activates the NLRP3-inflammasome via the calcium-sensing receptor in monocytes/macrophages primed by lipopolysaccharide, and this effect is mediated by the uptake of calciprotein particles (CPPs) formed out of calcium, phosphate, and fetuin-A. Aim of the study was to unravel the influence of calcium on monocytes when the priming signal is not present. Monocytes were isolated from the blood of healthy controls and RA patients. Macrophages were characterized using scRNA-seq, DNA microarray, and proteomics. Imaging flow cytometry was utilized to study intracellular events. Here we show that extracellular calcium and CPPs lead to the differentiation of monocytes into calcium-macrophages when the priming signal is absent. Additional growth factors are not needed, and differentiation is triggered by calcium-dependent CPP-uptake, lysosomal alkalization due to CPP overload, and TFEB- and STAT3-dependent increased transcription of the lysosomal gene network. Calcium-macrophages have a needle-like shape, are characterized by excessive, constitutive SPP1/osteopontin production and a strong pro-inflammatory cytokine response. Calcium-macrophages differentiated out of RA monocytes show a stronger manifestation of this phenotype, suggesting the differentiation process might lead to the pro-inflammatory macrophage response seen in the RA synovial membrane.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Rheumatoid-arthritis; Bone Erosion; Osteopontin; Fluid; Inflammation; Model; Destruction; Expression; Regulator
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Zeitschrift Cell Death & Disease
Quellenangaben Band: 13, Heft: 1, Seiten: , Artikelnummer: 53 Supplement: ,
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-506501-001
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)
DOI 10.1038/s41419-022-04507-3
WOS ID WOS:000742028800002
Scopus ID 85122834737
PubMed ID 35022393
Erfassungsdatum 2022-06-02
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