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Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes
David Haschka, … , Guenter Weiss, Piotr Tymoszuk
David Haschka, … , Guenter Weiss, Piotr Tymoszuk
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e98867. https://doi.org/10.1172/jci.insight.98867.
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Research Article Immunology Metabolism

Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes

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Abstract

Myelomonocytic cells are critically involved in iron turnover as aged RBC recyclers. Human monocytes are divided in 3 subpopulations of classical, intermediate, and nonclassical cells, differing in inflammatory and migratory phenotype. Their functions in iron homeostasis are, however, unclear. Here, we asked whether the functional diversity of monocyte subsets translates into differences in handling physiological and pathological iron species. By microarray data analysis and flow cytometry we identified a set of iron-related genes and proteins upregulated in classical and, in part, intermediate monocytes. These included the iron exporter ferroportin (FPN1), ferritin, transferrin receptor, putative transporters of non-transferrin-bound iron (NTBI), and receptors for damaged erythrocytes. Consequently, classical monocytes displayed superior scavenging capabilities of potentially toxic NTBI, which were augmented by blocking iron export via hepcidin. The same subset and, to a lesser extent, the intermediate population, efficiently cleared damaged erythrocytes in vitro and mediated erythrophagocytosis in vivo in healthy volunteers and patients having received blood transfusions. To summarize, our data underline the physiologically important function of the classical and intermediate subset in clearing NTBI and damaged RBCs. As such, these cells may play a nonnegligible role in iron homeostasis and limit iron toxicity in iron overload conditions.

Authors

David Haschka, Verena Petzer, Florian Kocher, Christoph Tschurtschenthaler, Benedikt Schaefer, Markus Seifert, Sieghart Sopper, Thomas Sonnweber, Clemens Feistritzer, Tara L. Arvedson, Heinz Zoller, Reinhard Stauder, Igor Theurl, Guenter Weiss, Piotr Tymoszuk

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Figure 4

Regulation of classical monocyte FPN1 by hepcidin and iron and its functionality.

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Regulation of classical monocyte FPN1 by hepcidin and iron and its funct...
(A and B) PBMCs (n = 3 healthy donors) were incubated with the indicated hepcidin concentrations (A) or 10 μM Fe3+ [B, Fe2(SO4)3]. Surface FPN1 levels in monocyte subsets were determined by flow cytometry. Monocyte subpopulations were defined as described in Supplemental Figure 2A (red: classical; gray: intermediate; blue: nonclassical monocytes). Representative signal histograms are shown (open histograms: isotype; tinted histograms: FPN1). Graphs display ΔMFI values; each point represents 1 measurement, bars denote mean, and error bars represent SEM. The cell donor is represented by symbol shape. Statistical significance was assessed with second-order (A) and first-order linear models (B); a separate model was applied to each monocyte subset. Estimates for the first-order hepcidin term (A) and for changes in FPN1 ΔMFI at particular time points (B) are shown with 95% CI. Estimate P values were calculated with 2-tailed t test. ANOVA for the first-order hepcidin term: P = 0.00023 (F1,12 = 27). ANOVA for the iron terms (B): classical monocytes: P = 0.00039 (F3,9 = 18); intermediate monocytes: P = 0.045 (F3,9 = 4); nonclassical monocytes: P = NS (F3,9 = 0.64). (C) 10 μM Fe3+-loaded CD14+ monocytes (n = 3 healthy donors) were incubated with 0.5 mg/ml apo-TF for the indicated time points. Apo-TF: holo-TF conversion in culture supernatant was monitored by absorbance measurements at 280 (A280) and 460 nm (A460). Culture medium without apo-TF served as a blank sample. Representative absorbance spectra are shown. Graphs depict absorbance values. Each point represents 1 measurement, bars denote mean, and error bars represent SEM. The cell donor is represented by symbol shape. Statistical significance was assessed with second-term linear models. Estimates for absorbance change rate are shown with 95% CI. Estimate P values were calculated with 2-tailed t test. ANOVA for the rate term: A280: P = 0.00013 (F1,9 = 40); A460: P < 0.0001 (F1,9 = 63).

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