Iron regulatory protein (IRP)–mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow

Author:

Bonadonna Michael12ORCID,Altamura Sandro3ORCID,Tybl Elisabeth14,Palais Gael1,Qatato Maria1ORCID,Polycarpou-Schwarz Maria1ORCID,Schneider Martin5,Kalk Christina1ORCID,Rüdiger Wibke1,Ertl Alina1,Anstee Natasha67ORCID,Bogeska Ruzhica67ORCID,Helm Dominic5ORCID,Milsom Michael D.67ORCID,Galy Bruno1ORCID

Affiliation:

1. German Cancer Research Center, “Division of Virus-Associated Carcinogenesis”, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

2. Biosciences Faculty, University of Heidelberg, 69120 Heidelberg, Germany.

3. University of Heidelberg, Department of Pediatric Hematology, Oncology and Immunology, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.

4. IB-Cancer Research Foundation, Science Park 2, 66123 Saarbrücken, Germany.

5. German Cancer Research Center, Mass Spectrometry based Protein Analysis Unit, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

6. Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

7. German Cancer Research Center, “Division of Experimental Hematology”, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Abstract

Iron is mostly devoted to the hemoglobinization of erythrocytes for oxygen transport. However, emerging evidence points to a broader role for the metal in hematopoiesis, including the formation of the immune system. Iron availability in mammalian cells is controlled by iron-regulatory protein 1 (IRP1) and IRP2. We report that global disruption of both IRP1 and IRP2 in adult mice impairs neutrophil development and differentiation in the bone marrow, yielding immature neutrophils with abnormally high glycolytic and autophagic activity, resulting in neutropenia. IRPs promote neutrophil differentiation in a cell intrinsic manner by securing cellular iron supply together with transcriptional control of neutropoiesis to facilitate differentiation to fully mature neutrophils. Unlike neutrophils, monocyte count was not affected by IRP and iron deficiency, suggesting a lineage-specific effect of iron on myeloid output. This study unveils the previously unrecognized importance of IRPs and iron metabolism in the formation of a major branch of the innate immune system.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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