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- Impact of H-ferritin deficiency on macrophage viability and iron statusPublication . Mesquita, Gonçalo Augusto Taborda da Costa Laranja; Moreira, Ana Carolina; Gomes, Maria Salomé; Arosa, Fernando AguilarAlmost all life on Earth has a great demand for iron. Importance of iron is based on its crucial participation on several fundamental processes such as DNA and RNA synthesis, cell proliferation and energy production. However, this mineral needs to be strictly controlled and properly stored, as free iron can induce tissue and cell damage through the formation of free radicals. Iron traffic and distribution is controlled by complex systems, operating both at systemic and at cellular levels. Ferritin plays a key role in this respect. The ferritin protein, composed of H and L subunits, is responsible for safely storing iron inside the cells. Macrophages are central cells both for immune response to infection and for the iron metabolism and distribution. Previous work of our group showed that macrophages infected with mycobacteria increase their content in H-ferritin (FTH1). The main goal of this thesis was to investigate the role of FTH1 in macrophage physiology, using bone marrow-derived macrophages from mice with a conditional deletion of Fth1 in the myeloid lineage. Our data showed that FTH1 was not necessary for macrophages’ differentiation from bone marrow precursors. FTH1-deficient macrophages kept their viability and had a normal expression of iron-related genes. Nonetheless, when challenged with exogenous iron, macrophages lacking Fth1 have increased mortality, probably due to the increase in free iron and subsequent increase in oxidative damage. Furthermore, the impact of Fth1 on macrophage response to both immune and bacterial stimuli was studied. Our results demonstrated a clear role for H-ferritin in protection against IFN-? toxicity, as cells that do not express Fth1 had their viability impaired alongside with higher mortality. Gene expression of iron metabolism-related genes, between genotypes, was altered, especially in cells treated with IFN-?+LPS. Additionally, nitrites production was hampered in macrophages lacking Fth1. In conclusion, these findings indicate that FTH1 is essential for cellular protection against iron and IFN-?-induced toxicity. Future work will deepen our knowledge onto the mechanisms behind the protective role of FTH1 in macrophages, against these different external insults, and also in the context of infection.