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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 10

Accumulation of labile iron and regulation of FPN1 in blood monocytes in iron overload diseases.

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Accumulation of labile iron and regulation of FPN1 in blood monocytes in...
(A and B) Blood samples (FPN: whole-blood leukocytes, calcein: PBMCs) were obtained from healthy controls (n = 18) and myelodysplastic syndrome (MDS) patients with or without hyperferritinemia (FTlo: serum ferritin <400 ng/ml, n = 7 and FThi: serum ferritin <400 ng/ml, n = 5). Surface FPN1 expression (A) and calcein fluorescence (B) in monocyte subpopulations were determined by flow cytometry. Monocyte subpopulations were defined as described in Supplemental Figure 10AB (red: classical; gray: intermediate; blue: nonclassical monocytes). Calcein MFI is assumed to be inversely proportional to LIP levels. Representative signal FPN1 and calcein histograms are shown (tinted histograms: specific staining, open histograms: isotype). Graphs show ΔMFI and MFI values. Each point represents 1 measurement, bars denote mean, and error bars represent SEM. Statistical significance for the healthy vs. MDS FTlo and MDS FTlo vs. MDS FThi comparisons were determined with first-order linear models. Separate models were applied to each monocyte subset. Estimate values with 95% CI are shown. Estimate P values were calculated with 2-tailed t test. ANOVA statistics are presented in Supplemental Table 6.

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