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    Neutrophils from hemochromatosis patients are protected from iron overload and are primed or pre-activated

    Team Carole Peyssonnaux

    Within Carole Peyssonnaux's team, Cyril Renassia characterized the regulation of intracellular iron and the impact of its deregulations on the function of neutrophils (immune cells) in a context of hemochromatosis.

    Published in Blood Advances, this study identifies the role of hepcidin in the maintenance of intracellular iron in neutrophils. In conditions of primary iron overload, such as hereditary hemochromatosis, the lack of hepcidin protects the neutrophil from excess of iron. Systemic iron overload is associated with a pre-activation of neutrophils.


    Iron is essential for the oxidative response of neutrophils by allowing the generation of reactive forms of oxygen by NADPH oxidase. The function of neutrophils has, however, been described as severely impaired under conditions of iron overload, in particular in patients receiving multiple transfusions. Therefore, regulation of iron homeostasis in the neutrophil appears to have a critical role in avoiding iron toxicity due to its high chemical reactivity. Hepcidin is the key regulatory hormone of iron homeostasis in the body. However, no study has investigated the role of this peptide in maintaining neutrophil iron homeostasis, or even characterized the function of neutrophils in patients with Hereditary Hemochromatosis (HH), a genetic disorder caused by a failure of hepcidin production, extremely common in the West. This defect in the production of hepcidin leads to uncontrolled recycling and absorption of iron, which causes iron deposition in the tissues during the life of the sick individual. This promotes the appearance of cardiovascular problems, hepatocarcinomas or the development of arthropathies. These different pathologies all involve a role of neutrophils. Understanding the iron homeostasis of the neutrophil and the functional consequences of its deregulation would allow better therapeutic precision, particularly with regard to the use of hepcidin mimetics.

    In this study, the team hypothesizes that in conditions of iron overload, the lack of hepcidin can lead to a maintenance of the export of intracellular iron from neutrophils, avoiding an accumulation of toxic iron for this major immune population. 


    The authors studied two models of iron overload: a model of dietary iron overload, in which the production of hepcidin is increased by a diet rich in iron; and a genetic model of iron overload, in which hepatic hepcidin is deleted.

    They show that the presence or absence of hepcidin in the bloodstream is decisive in conditions of systemic iron overload. When hepcidin is increased (food overload) the export of iron from neutrophils is reduced resulting in overloaded neutrophils, while when it is absent (genetic overload), the export of iron is maintained resulting in iron-poor neutrophils. Iron is essential for the oxidative burst of neutrophils and the authors show that an intracellular iron overload of the neutrophil leads to a decrease in the oxidative burst. On the contrary, the iron-poor neutrophils isolated from the genetic model show a higher oxidative activity. In order to understand whether this exacerbated activity is present in humans, neutrophils from hemochromatosis (HH) patients presenting the pathogenic C282Y variant of the hepcidin gene have been isolated. First, the iron content of the neutrophils of HH patients is normal while presenting, in the same way as in the genetic overload model, a surprising increase in oxidative burst. The authors therefore exclude a direct effect of the lack of iron on the oxidative burst under these conditions. In addition, they show that systemic iron overload correlates with an environment favorable to the priming, or preparation, of neutrophils in these patients. Indeed, the increase in TNFα, VCAM-1 and ICAM-1 in the plasma of HH patients is associated with a state of neutrophil priming, responsible for the increase in the observed burst. Finally, the characterization of the activation state of neutrophils obtained from HH patients is completed by the identification of an increased phagocytosis and a decrease in L-selectins at the surface of HH neutrophils in comparison to healthy donors.


    This study characterizes for the first time the homeostasis of iron in the major immune population of the human bloodstream, neutrophils. It shows that in conditions of systemic iron overload, the presence or absence of hepcidin is a determining element in the regulation of intracellular iron in neutrophils. This implies considering iron overloads, not as one unique type of pathology, but as quite distinct diseases. In particular, a multi-transfused patient presenting an increase in iron parameters associated with an increase in hepcidin will be likely to present neutrophils rich in iron and whose function is incidentally impaired, while a patient with hemochromatosis HFE will present neutrophils with physiological iron levels despite the patient's systemic iron overload. This leads to reconsidering the effect of adding hepcidin agonists in conditions of iron overload, taking into account a potential side effect on the function of immune cells, in particular neutrophils.



    Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed. Renassia C, Louis S, Cuvellier S, Boussetta N, Deschemin JC, Borderie D, Bailly K, Poupon J, Dang PM, El-Benna J, Manceau S, Lefrère F, Vaulont S, Peyssonnaux C. Blood Adv. 2020 Aug 25;4(16):3853-3863. doi:.10.1182/bloodadvances.2020002198


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