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

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...

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Autores principales: Murthy, Supriya, Karkossa, Isabel, Schmidt, Caroline, Hoffmann, Anne, Hagemann, Tobias, Rothe, Kathrin, Seifert, Olga, Anderegg, Ulf, von Bergen, Martin, Schubert, Kristin, Rossol, Manuela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755842/
https://www.ncbi.nlm.nih.gov/pubmed/35022393
http://dx.doi.org/10.1038/s41419-022-04507-3
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author Murthy, Supriya
Karkossa, Isabel
Schmidt, Caroline
Hoffmann, Anne
Hagemann, Tobias
Rothe, Kathrin
Seifert, Olga
Anderegg, Ulf
von Bergen, Martin
Schubert, Kristin
Rossol, Manuela
author_facet Murthy, Supriya
Karkossa, Isabel
Schmidt, Caroline
Hoffmann, Anne
Hagemann, Tobias
Rothe, Kathrin
Seifert, Olga
Anderegg, Ulf
von Bergen, Martin
Schubert, Kristin
Rossol, Manuela
author_sort Murthy, Supriya
collection PubMed
description 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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spelling pubmed-87558422022-01-20 Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages Murthy, Supriya Karkossa, Isabel Schmidt, Caroline Hoffmann, Anne Hagemann, Tobias Rothe, Kathrin Seifert, Olga Anderegg, Ulf von Bergen, Martin Schubert, Kristin Rossol, Manuela Cell Death Dis Article 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. Nature Publishing Group UK 2022-01-12 /pmc/articles/PMC8755842/ /pubmed/35022393 http://dx.doi.org/10.1038/s41419-022-04507-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Murthy, Supriya
Karkossa, Isabel
Schmidt, Caroline
Hoffmann, Anne
Hagemann, Tobias
Rothe, Kathrin
Seifert, Olga
Anderegg, Ulf
von Bergen, Martin
Schubert, Kristin
Rossol, Manuela
Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages
title Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages
title_full Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages
title_fullStr Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages
title_full_unstemmed Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages
title_short Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages
title_sort danger signal extracellular calcium initiates differentiation of monocytes into spp1/osteopontin-producing macrophages
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755842/
https://www.ncbi.nlm.nih.gov/pubmed/35022393
http://dx.doi.org/10.1038/s41419-022-04507-3
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