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    Roles of hepcidin-iron axis on innate immunity in two pathological contexts: the Hereditary Hemochromatosis and the Inflammatory Bowel Diseases


    Cyril Renassia

     

    March 19th 2 pm 2020

    Rosalind Franklin room, 2nd floor

    Institut Cochin, 22 rue Méchain, Paris 75014


    Supervisor: Carole Peyssonnaux

    Team: Iron and Immunity    

    Department: Endocrinologie, Métabolisme et Diabète (EMD)
    Abstract:

    Iron is essential for all living organisms, as co-factor for major biological processes such as oxygen transportation, mitochondrial function, cell proliferation and DNA replication. The key iron regulator hepcidin acts as a repressor of both cellular iron export and intestinal iron absorption. The Hereditary Hemochromatosis (HH) is the most frequent genetic disorder in Occident, affecting between 1/200 to 1/2000 in France depending on the geographic area. Mutations involved in Hereditary Hemochromatosis impair hepcidin production. In more than 90% cases, the loss of function of HFE regulator leads to uncontrolled iron absorption. Thus, iron deposit in organs damages tissues and cells. However, iron overload has been linked to impaired immune functions, particularly affecting neutrophils but nothing is known about the neutrophil functions in Hereditary Hemochromatosis. This study characterizes the iron homeostasis in neutrophils and compares the capacity of neutrophils to defend the host in two different iron overload contexts: the genetic iron overload without hepcidin production and the experimentally-induced iron overload with strong hepcidin expression. We show that lack of hepcidin protects neutrophils from iron accumulation and consecutive dysfunctions. Moreover, we identified an hyperactivation state of neutrophils isolated from both HH mouse model and patients mutated on HFE.

    As hepcidin has been first identified as an antimicrobial peptide, I investigated, in the second part of my thesis, its role in the development of Inflammatory Bowel Diseases (IBDs) via a role both as local iron regulator and immunomodulator. We demonstrated that Dendritic Cell-derived hepcidin induces the iron sequestration in intestinal phagocytes resulting in modification of intestinal healing as well as microbiota diversity and richness in experimental models of colitis. Moreover, we found that hepcidin is highly expressed by intestinal epithelial cells (IEC) Crohn's and Ulcerative Colitis patients. We aimed to understand the role of this IEC-derived hepcidin in response to adherent bacteria like C. rodentium. We observed that hepcidin doesn't display direct bactericidal activity but participates to the regulation of mucosal immunity in IBDs.

     

     

    Keywords :

    hepcidin - iron - hemochromatosis - neutrophil - IBD - inflammatory Bowel Diseases - colitis - innate immunity