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

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

  • Cell Death Dis. 2022 Jan 12;13(1):53. doi: 10.1038/s41419-022-04507-3.
Supriya Murthy 1,  Isabel Karkossa 2,  Caroline Schmidt 1,  Anne Hoffmann 3,  Tobias Hagemann 3,  Kathrin Rothe 1,  Olga Seifert 1,  Ulf Anderegg 4,  Martin von Bergen 2 5 6,  Kristin Schubert 2,  Manuela Rossol 7
Affiliations

Affiliations

  • 1 Devision of Rheumatology, Department of Endocrinology, Nephrology, Rheumatology, Leipzig University, 04103, Leipzig, Germany.
  • 2 Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research GmbH, 04318, Leipzig, Germany.
  • 3 Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103, Leipzig, Germany.
  • 4 Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Universität Leipzig, 04103, Leipzig, Germany.
  • 5 Institute for Biochemistry, Faculty of Life Sciences, Leipzig University, 04318, Leipzig, Germany.
  • 6 German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, 04103, Leipzig, Germany.
  • 7 Devision of Rheumatology, Department of Endocrinology, Nephrology, Rheumatology, Leipzig University, 04103, Leipzig, Germany. manuela.rossol@medizin.uni-leipzig.de.
PMID: 35022393 DOI: 10.1038/s41419-022-04507-3
Abstract

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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