Iron homeostasis in immune mononuclear cells : a potential role in a atherogenesis

Tese de doutoramento, Biologia (Biologia-Molecular), Universidade de Lisboa, Faculdade de Ciências, 2015

Atherosclerosis is an inflammatory disease characterized by the formation of vessel wall plaques, initiated by oxidized LDL (oxLDL) accumulation and infiltration of immune cells. Iron accumulation in atherosclerotic plaques was proposed to constitute a risk factor in atherogenesis and immune cells could contribute to this risk. Herein, we studied the iron homeostasis of lymphocytes, monocytes and macrophages in a context of atherogenic conditions. Particularly, we investigated the expression and regulation of the iron exporter ferroportin-1 (Fpn1) and its potential functional partner ceruloplasmin (Cp). We demonstrated that lymphocytes, monocytes and macrophages express both a soluble Cp and a membrane GPI-Cp. Through oxidation of LDL, Cp expressed by immune cells could contribute to the reported association between high Cp levels and increased cardiovascular risk. We showed that GPI-Cp partially co-localizes with Fpn1 in lipid rafts of iron-treated macrophages and could participate in Fpn1-mediated iron export. However, we proposed that besides Cp, the β-amyloid precursor protein (APP) could be a functional partner of Fpn1 in macrophages that needs to be further studied. The effect of oxLDL on the iron homeostasis was investigated in macrophages. Despite oxLDL-driven Nrf2 activation and increased heme oxygenase-1 expression, Mox macrophages were not protected from foam cell formation like Mhem/M(Hb) macrophages, showing lipid accumulation, basal levels of Fpn1 at cell surface along with upregulation of interleukine-6 and hepcidin. Simultaneous exposure to oxLDL and LPS/IFNγ induced a Mox/M1 phenotype closer to M1 than Mox, with increased interleukine-6 and H-ferritin expression along with decreased Fpn1 expression. Our results suggest that macrophages exposed to a microenvironment rich in oxLDL and pro-inflammatory cytokines are prone to accumulate both lipids and iron while secreting high levels of pro-inflammatory cytokines and Cp, which will further promote the local inflammation and LDL oxidation. In summary, our results support the “iron hypothesis” in atherogenesis proposed by Sullivan.

Fundação para a Ciência e a Tecnologia (FCT)