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Ferritin-associated iron induces neutrophil dysfunction in hemosiderosis
B Cantinieaux1, A Janssens, J R Boelaert
1Department of Haematology, CHU Saint-Pierre, ULB, Brussels, Belgium.
Abstract:
Neutrophils (PMNs) from patients with secondary iron overload have an increased iron and ferritin content as well as a phagocytosis defect. Several serum components might be incriminated in the cellular iron accumulation. We therefore compared the effects on the PMN phagocytosis of total serum as well as the ferritin and transferrin fractions of serum derived from patients with thalassemia major and healthy control subjects. An incubation system of PMNs was developed. PMN phagocytosis was measured before and after incubation. Total serum from patients with thalassemia induced a defect that was prevented by co-incubation with deferoxamine (DFO). Gel-filtration chromatography was performed to separate the serum fraction containing transferrin and albumin from that containing ferritin. The transferrin-albumin fraction had no effect on PMN phagocytosis. On the contrary, the ferritin fraction of normal serum was deleterious to PMN phagocytosis, and the same fraction from thalassemic serum decreased PMN phagocytosis even more. Co-incubation with DFO or catalase improved this defect. Moreover, a cellular increase in the L-type subunit of ferritin was observed after the incubation of PMNs with the ferritin-containing fraction from thalassemic serum. In conclusion, serum from patients with thalassemia is toxic to PMNs, and this toxicity is due to ferritin-associated iron.
Insights
Serum ferritin in thalassemia patients impairs neutrophil function. This iron-associated toxicity affects phagocytosis, but can be mitigated by deferoxamine or catalase treatments.
Area of Science:
- Hematology
- Immunology
- Biochemistry
Background:
- Neutrophils (PMNs) in secondary iron overload conditions exhibit elevated iron and ferritin levels, alongside impaired phagocytosis.
- Serum components are suspected contributors to cellular iron accumulation in these patients.
Purpose of the Study:
- To investigate the impact of serum components, specifically ferritin and transferrin, from thalassemia major patients on neutrophil phagocytosis compared to healthy controls.
- To elucidate the role of ferritin-associated iron in neutrophil dysfunction.
Main Methods:
- Developed an in vitro system to incubate neutrophils (PMNs) with patient and control serum fractions.
- Utilized gel-filtration chromatography to isolate transferrin-albumin and ferritin serum fractions.
- Quantified PMN phagocytosis before and after incubation with different serum components.
- Assessed the effects of deferoxamine (DFO) and catalase co-incubation.
Main Results:
- Total serum from thalassemia patients significantly reduced PMN phagocytosis, an effect reversed by DFO.
- The ferritin-rich serum fraction, particularly from thalassemic patients, markedly decreased PMN phagocytosis.
- Co-incubation with DFO or catalase ameliorated the phagocytic defect induced by the ferritin fraction.
- Incubation with thalassemic ferritin fraction led to increased cellular L-type ferritin subunit.
Conclusions:
- Serum from thalassemia major patients exerts toxicity on neutrophils, primarily due to ferritin-associated iron.
- Ferritin, rather than transferrin, is the key serum component responsible for the phagocytic defect in neutrophils.
- Iron chelation therapy (DFO) and antioxidant treatment (catalase) show potential in counteracting ferritin-induced neutrophil dysfunction.