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Intracellular Fe enhances monocyte adhesion to TNF-a-activated endothelium under physiological flow and MCP-1-dependent transendothelial migration

Infiltration of monocytes across the endothelial barrier is not only considered to contribute to the initiation but also to the progression of atherosclerosis. Given the plausible roles of iron in inflammatory processes, we have investigated the effects of iron on monocyte-endothelial cell interactions.

Monocyte rolling and firm adhesion to TNF-a-activated endothelial cells were performed in a physiological flow model, while their diapedesis was assessed by an in vitro transendothelial migration assay. The expression of surface proteins and the formation of intracellular radicals were measured by flow cytometry. Iron enhanced TNF-a-induced endothelial activation, resulting in a rise on monocyte adhesion. Moreover, an increase in adhesion was observed using iron-loaded monocytes compared to controls. Blockade of the integrins, VLA-4 and LFA-1, restored more than 60% of monocyte rolling.

However, in this condition, the number of firmly adhered cells was higher for iron-loaded monocytes than controls, while no difference in the rolling velocity was observed, suggesting that iron could have affected receptors other than the blocked integrins. Iron loading indeed upregulated CCR-2 and CXCR-2 but not PECAM-1 expression on monocytes, and resulted in increased MCP-1-dependent transendothelial migration. Furthermore, both iron-induced adhesion and transmigration could be mitigated by iron chelation. Additionally, accumulation of oxygen-derived radicals due to iron loading was evidenced.

Conclusion: We conclude that intracellular iron is an important enhancer of cytokine-mediated consecutive processes of monocyte-endothelial interactions. This finding reveals an immunomodulatory function of iron in inflammation.

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