Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo
Ivona T. Olszak, … , Edward M. Brown, David T. Scadden
Ivona T. Olszak, … , Edward M. Brown, David T. Scadden
Published May 1, 2000
Citation Information: J Clin Invest. 2000;105(9):1299-1305. https://doi.org/10.1172/JCI9799.
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Article

Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo

Abstract

Recruitment of macrophages to sites of cell death is critical for induction of an immunologic response. Calcium concentrations in extracellular fluids vary markedly, and are particularly high at sites of injury or infection. We hypothesized that extracellular calcium participates in modulating the immune response, perhaps acting via the seven-transmembrane calcium-sensing receptor (CaR) on mature monocytes/macrophages. We observed a dose-dependent increase in monocyte chemotaxis in response to extracellular calcium or the selective allosteric CaR activator NPS R-467. In contrast, monocytes derived from mice deficient in CaR lacked the normal chemotactic response to a calcium gradient. Notably, CaR activation of monocytes bearing the receptor synergistically augmented the transmigration response of monocytes to the chemokine MCP-1 in association with increased cell-surface expression of its cognate receptor, CCR2. Conversely, stimulation of monocytes with MCP-1 or SDF-1α reciprocally increased CaR expression, suggesting a dual-enhancing interaction of Ca2+ with chemokines in recruiting inflammatory cells. Subcutaneous administration in mice of Ca2+, MCP-1, or (more potently) the combination of Ca2+ and MCP-1, elicited an inflammatory infiltrate consisting of monocytes/macrophages. Thus extracellular calcium functions as an ionic chemokinetic agent capable of modulating the innate immune response in vivo and in vitro by direct and indirect actions on monocytic cells. Calcium deposition may be both consequence and cause of chronic inflammatory changes at sites of injury, infection, and atherosclerosis.

Authors

Ivona T. Olszak, Mark C. Poznansky, Richard H. Evans, Douglas Olson, Claudine Kos, Martin R. Pollak, Edward M. Brown, David T. Scadden

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Figure 1

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(a) CD14+ monocytes stain positively for the CaR, and binding of anti-Ca...
(a) CD14+ monocytes stain positively for the CaR, and binding of anti-CaR antibody is inhibitable by preincubation with CaR peptide. Purified CD14+ PBMC (scattergram: vertical axis is log fluorescence with allophycocyanin-conjugated anti-CD14; horizontal axis is side scatter) were exposed to anti-CaR antibody (right panel; solid histogram) or isotype control (open histogram) and examined by flow cytometry. Monocytes were also preincubated with CaR peptide before staining with anti-CaR antibody (dashed histogram). Veritical axis is number of events; horizontal axis is log fluorescence with fluorescein isothiocyanate–conjugated anti-CaR. Data represent one of ten independent experiments with comparable results. (b) Elevating the extracellular Ca2+ concentration or adding the selective CaR activator NPS R-467 induces elevation of cytosolic Ca2+. Sustained increases in cytosolic Ca2+ were seen in response to 4.5 mM Ca2+, or 1 μM NPS R-467 or S-467 in the presence of 1.5 mM Ca2+. All calcium concentrations shown represent the total calcium content of the basal medium plus added calcium. Data are from one of three independent experiments with similar results.