|Our team “Hypoxia and iron homeostasis” generated new genetic models to investigate the role of 1) HIFs (Hypoxia Inducible Factors), central mediators of cellular adaptation to hypoxia and of 2) hepcidin, the major iron regulatory hormone, in pathophysiological conditions.|
Iron is an essential element in all living organisms, required as a cofactor for the oxygen-binding proteins such as hemoglobin, into red blood cells. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly interconnected.
Given the links between oxygen transport and iron metabolism, associations between the physiology of hypoxic response, and the control of iron availability need to take place. HIF transcription factors are central mediators of cellular adaptation to critically low oxygen levels (=hypoxia). Our team unravels the role of HIF-2 in iron metabolism as critical regulators of iron absorption in the intestine and in systemic iron homeostasis by downregulating hepcidin, the major iron regulatory hormone.
Based on new genetics models we have generated, our objectives are to :
1) define the physiological roles of HIF and hepcidin in different key organs involved in maintaining body iron homeostasis.
2) study the role of hepcidin during bacterial infection and tumorigenesis, two pathological conditions where iron is critically required for the proliferation of the pathogens and for cancer cells.
Role of hepcidin in pathophysiological conditions
Iron is an essential nutrient and is critical for a multitude of biological processes including oxygen delivery. Both iron excess and iron scarcity have important consequences. Excess iron accumulation is observed in hereditary hemochromatosis, the most common genetic disorder of humans, while iron deficiency is one of the most frequently observed diseases in the world today, affecting as many as two billion people. As excess iron is not excreted, it use and storage needs to be tightly regulated at the level of intestinal absorption.
Hepcidin, a 25 amino acid peptide, has been demonstrated to be the iron regulatory hormone, capable of blocking iron absorption from the intestine and iron release from macrophages. Its expression is induced by iron accumulation and diminished in situations of iron needs (anemia, hypoxia). Hepcidin controls serum iron levels by binding ferroportin, the only known iron exporter, and inducing its degradation. Mutations affecting hepcidin expression can cause hemochromatosis, a common genetic disorder.
Hepcidin is produced mainly by the liver, but many tissues have been described as being capable of expressing hepcidin : macrophages, brain, heart, retina, kidney, adipocyte, pancreas. However, the contribution of these tissues on circulating hepcidin and the impact of hepcidin deficiency in different tissues with regards to iron homeostasis is unknown. In order to determine the role of these hepcidin-producing tissues, we have generated mice with floxed hamp1 alleles allowing tissue-specific gene deletion with the classical Cre-loxP strategy (Zumerle et al., Blood, 2014). Using this model, we demonstrated that hepcidin deletion specifically in the liver recapitulated characteristics of hemochromatosis, mimicking the iron overload phenotype of total hepcidin KO mice. More surprisingly, we found undetectable plasma hepcidin levels, indicating that cell types other than hepatocytes contribute negligibly to circulating hepcidin and suggesting novel, unanticipated roles, for locally produced hepcidin.
This new mouse model, in which the hepcidin gene can be spatiotemporally inactivated will be important for future research to determine the impact of hepcidin deficiency in different tissues in pathophysiological conditions (inflammation, infection, cancer…)
Role of HIF-2 in iron homeostasis
Hypoxia-inducible transcription factors (HIF)-1 and HIF-2, composed of an oxygen-dependent alpha-subunit and a constitutive beta-subunit, have been characterized as the most important regulators of oxygen homeostasis during physiological and pathological conditions. HIF activity is induced in response to hypoxia (low levels of oxygen) and mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF regulates the expression of multiple genes encoding key components of the response pathway.
We have shown, by using genetic mouse models that HIF-2 played a crucial role in maintaining iron balance in the organism. HIF-2 regulates the expression of iron absorption genes in the intestine: DMT1 and ferroportin (figure) and the consecutive level of serum iron (Mastrogiannaki et al., JCI, 2009).
To address the contribution of HIF-2 in a model of pathological increased iron absorption, we generated hepcidin KO mice (a murine model of hemochromatosis) lacking HIF-2 in the intestine and showed that the deletion of duodenal HIF-2 was beneficial in the development of the disease by decreasing the severity of the tissue iron loading in the hepcidin KO mice (Mastrogiannaki et al., Blood, 2012). Altogether, these results highlight the essential role of duodenal HIF-2 in regulating iron absorption and tissue iron accumulation in pathophysiology.
Matak P, Heinis M, Mathieu JR, Corriden R, Cuvellier S, Delga S, Mounier R, Rouquette A, Raymond J, Lamarque D, Emile JF, Nizet V, Touati E, Peyssonnaux C. Myeloid HIF-1 is protective in Helicobacter pylori-mediated gastritis. J Immunol. 2015 Apr 1;194(7):3259-66.
Zumerle S, Mathieu JR, Delga S, Heinis M, Viatte L, Vaulont S, Peyssonnaux C. Targeted disruption of hepcidin in the liver recapitulates the hemochromatotic phenotype. Blood. 2014 Jun 5;123(23):3646-50.
Mastrogiannaki M, Matak P, Delga S, Deschemin JC, Vaulont S, Peyssonnaux C. Deletion of HIF-2α in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice. Blood. 2012 Jan 12;119(2):587-90.
Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 2009 May;119(5):1159-66.
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007 Jul;117(7):1926-32.
Peyssonnaux C, Datta V, Cramer T, Doedens A, Theodorakis EA, Gallo RL, Hurtado-Ziola N, Nizet V, Johnson RS. HIF-1alpha expression regulates the bactericidal capacity of phagocytes. J Clin Invest. 2005 Jul;115(7):1806-15.
Awards and grants
Member of the labex GREX « The red cell: from genesis to death ».
Member of the DHU (Département Hospitalo-Universitaire) AUTHORS « maladies hormonales et auti-immunes »