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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 6

Hepcidin-enhanced NTBI clearance by classical and intermediate monocytes.

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Hepcidin-enhanced NTBI clearance by classical and intermediate monocytes...
(A) CD14+ monocytes (n = 6 healthy donors) were cultured with 10 μM Fe3+ [Fe2(SO4)3] with/without 2 μg/ml hepcidin. NTBI concentration in supernatant and NTBI uptake rate at the indicated time points were determined. On the graphs, 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 a first-order linear model. Estimates for the baseline NTBI concentration, changes in concentration at the particular time points, and for differences in concentration between control and hepcidin-stimulated samples are shown with 95% CI. Estimate P values were calculated with 2-tailed t test. ANOVA for the time and time-hepcidin interaction terms: Ptime = 0.00057 (F5,30 = 6.7), Ptime-hepcidin = NS (0.13) (F5,30 = 1.9). (B) CD14+ monocytes (n = 4 healthy donors) were stimulated with 0.5 μM 59Fe3+ (TBI) or 0.5 μM 59Fe3+ and 10 μM 56Fe3+ (NTBI) with/without 2 μg/ml hepcidin for 4 hours. 59Fe-ferritin in cell lysates was visualized by autoradiography. Autoradiograms and densitometry results are shown (colored symbols: control, open symbols: hepcidin). On the graphs, each point represents 1 measurement, bars denote mean, and error bars represent SEM. The cell donor is represented by symbol shape. Statistical significance was estimated with a first-order linear model. Estimates for changes in 59Fe-ferritin levels between culture conditions are shown with 95% CI. Estimate P values were calculated with 2-tailed t test. ANOVA for the NTBI, hepcidin, and NTBI-hepcidin interaction terms: PNTBI < 0.0001 (F1,12 = 113), Phepcidin = NS (F1,12 = 1.2), PNTBI: hepcidin = NS (F1,12 = 0.92).

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