DIFFERENT IRON SOURCES AND ACQUISITION PATHWAYS SHAPE MACROPHAGES TOWARDS OPPOSING FUNCTIONAL PHENOTYPES
Author(s): ,
Francesca Vinchi
Affiliations:
Molecular Medicine Partnership Unit (MMPU),University of Heidelberg & EMBL,Heidelberg,Germany
,
Richard Sparla
Affiliations:
Molecular Medicine Partnership Unit (MMPU),University of Heidelberg & EMBL,Heidelberg,Germany
,
Emanuela Tolosano
Affiliations:
Molecular Biotechnology Center,University of Turin,Turin,Italy
,
Uwe Platzbecker
Affiliations:
University Clinic Dresden,Dresden,Germany
Martina U. Muckenthaler
Affiliations:
Molecular Medicine Partnership Unit (MMPU),University of Heidelberg & EMBL,Heidelberg,Germany
(Abstract release date: May 18, 2017) EHA Learning Center. Vinchi F. Jun 25, 2017; 182100
Dr. Francesca Vinchi
Dr. Francesca Vinchi
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Abstract
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Abstract: S813

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15

Location: Room N109

Background

Iron homeostasis and macrophage biology are closely interconnected.  On the one hand, reticulo-endothelial macrophages are central for the regulation of iron homeostasis. The phagocytosis and degradation of senescent red blood cells (RBC) by macrophages enable efficient recycling of iron and the maintenance of systemic iron balance. On the other hand, iron exerts multiple effects on macrophage polarization and functionality. Macrophages exhibit a remarkable functional plasticity, reflected in their capacity to integrate diverse signals from the microenvironment and acquire distinct phenotypes. Macrophage polarization has been shown to dictate the expression of iron-regulated genes and determine cell iron handling.

Aims

Increasing evidence shows that iron availability itself has significant effects on immune effector functions and macrophage polarization. However, it is still unclear how different iron sources and acquisition pathways affect macrophage phenotypes.

Methods

To investigate this aspect, we analyzed both in vivo and in vitro, and compared the phenotypic switching of macrophages induced by different iron sources, including heme and iron, as well as hemolytic or intact RBCs.

Results

Hemolytic RBCs, free heme and iron-dextran treatment in mice shape macrophage polarization towards an M1-like pro-inflammatory phenotype. Splenic and hepatic macrophages from treated mice show iron deposition and increased expression of iron-related genes (ferroportin, ferritin, HO-1). Moreover, in these cells, the expression of M1 markers such as MHCII, CD86 and pro-inflammatory cytokines (TNFa, IL-6, IL-1b) is strongly increased, whereas the expression of M2 markers such as CD206, Arg-1 and IL-10 was significantly suppressed. Consistent results have been obtained treating bone marrow-derived macrophages with hemolytic RBCs, free heme and Fe-NTA. Importantly, the addition of the heme scavenger hemopexin and the iron carrier transferrin or the chelator deferoxamine fully abolish the ability of free heme and iron to trigger M1 polarization.
On the contrary, RBC transfusions in mice shape macrophages towards an M2-like anti-inflammatory phenotype. After three transfusions, serum iron and hepcidin levels significantly rise, and tissues as well as macrophages are heavily iron loaded. Macrophages show a drastic suppression of M1 markers and inflammatory cytokines, and induction of M2 markers. Interestingly, repeated transfusions result in extensive macrophage cell death and new monocytes recruitment in both liver and spleen.

Conclusion

Collectively, these results suggest that the source and route of iron acquisition have a key role in shaping macrophage phenotype, and demonstrate a dynamic role of iron overload in determining macrophage polarization and function. When iron is provided in the form of free heme or non-transferrin bound iron, it exerts a clear pro-inflammatory effect on macrophages; whereas when provided via a controlled physiological acquisition pathway such as erythrophagocytosis, it dampens macrophage immune effector functions, being its clearance activity more active.
Our findings have potential implications, on one side, for hemolytic diseases, where RBC hemolysis and elevated circulating heme might promote a detrimental chronic inflammatory state, and, on the other one, for infectious diseases, where free heme and iron, released upon cell damage, might boost inflammation and enhance resistance to infections. Conversely, accelerated RBC clearance, by suppressing macrophage pro-inflammatory response, is rather expected to promote infections in transfused individuals.

Session topic: 28. Iron metabolism, deficiency and overload

Keyword(s): Immunosuppression, Hemolysis, transfusion, Macrophage

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