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Intracellular labile iron promotes firm adhesion of human monocytes to endothelium under flow and transendothelial migration

Iron and monocyte–endothelial cell interactions

      Abstract

      Monocyte infiltration across the endothelium is part of the innate immune response, however it may contribute to severity of chronic conditions. We have investigated the effects of iron on the cytokine-mediated recruitment of monocytes to the endothelium, using a physiological flow model and a monocyte transendothelial migration model.
      Under flow, iron loading to endothelial cells promoted an increased number of tumor necrosis factor-α-mediated firm arrest of human monocytes. Similarly, an increased number of firmly adhered monocytes were observed in conditions in which monocytes were iron-loaded, compared to the non-iron-loaded conditions. In both iron-loaded and non-iron-loaded conditions, blockade of the α4 and β2 integrins restored similar number and velocity of monocyte rolling, suggesting that iron did not modulate rolling interactions. However, with the integrin blockade, the number of firmly adhered cells remained higher in iron-loaded conditions than in control conditions, suggesting that iron could have modulated receptors other than the blocked integrins to promote firm arrest. Iron loading indeed upregulated expression of chemokine receptors, CC receptor-2 and CXC receptor-2, but not platelet endothelial cell adhesion molecule-1. This effect concomitantly promoted monocyte chemotactic protein-1-dependent transendothelial migration. In addition, iron-induced firm adhesion and transmigration were counteracted by iron chelation. These data reveal an immunomodulatory function of iron in the cascade of events of cytokine-mediated monocyte infiltration across endothelium, and therefore suggests the role for iron in inflammatory conditions underlying diseases like atherosclerosis and neurodegeneration.

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