Journal
CELL DEATH & DISEASE
Volume 13, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-022-04507-3
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Funding
- German Research Foundation [RO 4037/3-1]
- DFG, German Research Foundation [403224013-SFB 1382-A05]
- Projekt DEAL
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This study reveals the mechanism by which extracellular calcium and calciprotein particles (CPPs) induce the differentiation of monocytes into calcium-macrophages in the absence of a priming signal. This differentiation process may contribute to the pro-inflammatory macrophage response observed in the synovial membrane of rheumatoid arthritis (RA) patients.
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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