Involvement of hepcidin in iron metabolism dysregulation in Gaucher disease
Thibaud Lefebvre,
Niloofar Reihani,
Raed Daher,
Thierry Billette de Villemeur,
Nadia Belmatoug,
Christian Rose,
Yves Colin-Aronovicz,
Hervé Puy,
Caroline Le Van Kim,
Mélanie Franco,
Zoubida Karim
Affiliations
Thibaud Lefebvre
University Sorbonne Paris Cité, Paris Diderot University, Inserm U1149 / ERL 8252, Inflammation Research Center (CRI), Laboratory of Excellence GR-Ex, Paris, France;AP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France
Niloofar Reihani
University Sorbonne Paris Cité, Paris Diderot University, Inserm, INTS, “Biologie Intégrée du Globule Rouge” Department, Laboratory of Excellence GR-Ex, Paris, France
Raed Daher
University Sorbonne Paris Cité, Paris Diderot University, Inserm U1149 / ERL 8252, Inflammation Research Center (CRI), Laboratory of Excellence GR-Ex, Paris, France
Thierry Billette de Villemeur
Sorbonne Universités, UPMC, GRC ConCer-LD and AP-HP, Hôpital Trousseau, Service de Neuropédiatrie, Centre de Référence des Maladies Lysosomales, Paris, France
Nadia Belmatoug
Hôpitaux Universitaires Paris Nord Val de Seine, Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Service de Médecine Interne, Centre de Référence des Maladies Lysosomales, Clichy, France
Christian Rose
Université Catholique de Lille, Hôpital Saint Vincent de Paul, Service d’Hématologie, France
Yves Colin-Aronovicz
University Sorbonne Paris Cité, Paris Diderot University, Inserm, INTS, “Biologie Intégrée du Globule Rouge” Department, Laboratory of Excellence GR-Ex, Paris, France
Hervé Puy
University Sorbonne Paris Cité, Paris Diderot University, Inserm U1149 / ERL 8252, Inflammation Research Center (CRI), Laboratory of Excellence GR-Ex, Paris, France;AP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France
Caroline Le Van Kim
University Sorbonne Paris Cité, Paris Diderot University, Inserm, INTS, “Biologie Intégrée du Globule Rouge” Department, Laboratory of Excellence GR-Ex, Paris, France
Mélanie Franco
University Sorbonne Paris Cité, Paris Diderot University, Inserm, INTS, “Biologie Intégrée du Globule Rouge” Department, Laboratory of Excellence GR-Ex, Paris, France
Zoubida Karim
University Sorbonne Paris Cité, Paris Diderot University, Inserm U1149 / ERL 8252, Inflammation Research Center (CRI), Laboratory of Excellence GR-Ex, Paris, France
Gaucher disease (GD) is an inherited deficiency of glucocerebrosidase leading to accumulation of glucosylceramide in tissues such as the spleen, liver, and bone marrow. The resulting lipid-laden macrophages lead to the appearance of “Gaucher cells”. Anemia associated with an unexplained hyperferritinemia is a frequent finding in GD, but whether this pathogenesis is related to an iron metabolism disorder has remained unclear. To investigate this issue, we explored the iron status of a large cohort of 90 type I GD patients, including 66 patients treated with enzyme replacement therapy. Ten of the patients treated with enzyme replacement were followed up before and during treatment. Serum levels of hepcidin, the iron regulatory peptide, remained within the physiological range, while the transferrin saturation was slightly decreased in children. Inflammation-independent hyperferritinemia was found in 65% of the patients, and Perl’s staining of the spleen and marrow smear revealed iron accumulation in Gaucher cells. Treated patients exhibited reduced hyperferritinemia, increased transferrin saturation and transiently increased systemic hepcidin. In addition, the hepcidin and ferritin correlation was markedly improved, and, in most patients, the hemoglobin level was normalized. To further explore eventual iron sequestration in macrophages, we produce a Gaucher cells model by treating the J774 macrophage cell line with a glucocerebrosidase inhibitor and showed induced local hepcidin and membrane retrieval of the iron exporter, ferroportin. These data reveal the involvement of Gaucher cells in abnormal iron sequestration, which may explain the mechanism of hyperferritinemia in GD patients. Local hepcidin-ferroportin interaction was involved in this pathogenesis.
