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

Iron and monocyte–endothelial cell interactions


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N Engl J Med. 2005; 352: 1685-1695
        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-116
        • Han M.K.
        • McLaughlin V.V.
        • Criner G.J.
        • Martinez F.J.
        Pulmonary diseases and the heart.
        Circulation. 2007; 116: 2992-3005
        • Zlokovic B.V.
        The blood–brain barrier in health and chronic neurodegenerative disorders.
        Neuron. 2008; 57: 178-201
        • Liao F.
        • Ali J.
        • Greene T.
        • Muller W.A.
        Soluble domain 1 of platelet–endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo.
        J Exp Med. 1997; 185: 1349-1357
        • Gerszten R.E.
        • Garcia-Zepeda E.A.
        • Lim Y.C.
        • et al.
        MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions.
        Nature. 1999; 398: 718-723
        • Shamri R.
        • Grabovsky V.
        • Gauguet J.M.
        • et al.
        Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines.
        Nat Immunol. 2005; 6: 497-506
        • Gu L.
        • Okada Y.
        • Clinton S.K.
        • et al.
        Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor-deficient mice.
        Mol Cell. 1998; 2: 275-281
        • Boring L.
        • Gosling J.
        • Cleary M.
        • Charo I.F.
        Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis.
        Nature. 1998; 394: 894-897
        • Boisvert W.A.
        • Santiago R.
        • Curtiss L.K.
        • Terkeltaub R.A.
        A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice.
        J Clin Invest. 1998; 101: 353-363
        • Kartikasari A.E.
        • Georgiou N.A.
        • Marx J.J.
        Iron intake and cardiovascular disease.
        in: Arnoldi A. Functional foods, cardiovascular disease and diabetes. Woodhead Publishing Ltd., Abington, Cambridge, UK and CRC Press LLC, Boca Raton, FL, USA2004: 99-125
        • Araujo J.A.
        • Romano E.L.
        • Brito B.E.
        • et al.
        Iron overload augments the development of atherosclerotic lesions in rabbits.
        Arterioscler Thromb Vasc Biol. 1995; 15: 1172-1180
        • Lee T.S.
        • Shiao M.S.
        • Pan C.C.
        • Chau L.Y.
        Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice.
        Circulation. 1999; 99: 1222-1229
        • Matthews A.J.
        • Vercellotti G.M.
        • Menchaca H.J.
        • et al.
        Iron and atherosclerosis: inhibition by the iron chelator deferiprone (L1).
        J Surg Res. 1997; 73: 35-40
        • Minqin R.
        • Rajendran R.
        • Pan N.
        • et al.
        The iron chelator desferrioxamine inhibits atherosclerotic lesion development and decreases lesion iron concentrations in the cholesterol-fed rabbit.
        Free Radic Biol Med. 2005; 38: 1206-1211
        • Stadler N.
        • Lindner R.A.
        • Davies M.J.
        Direct detection and quantification of transition metal ions in human atherosclerotic plaques: evidence for the presence of elevated levels of iron and copper.
        Arterioscler Thromb Vasc Biol. 2004; 24: 949-954
        • Roest M.
        • van der Schouw Y.T.
        • de Valk B.
        • et al.
        Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women.
        Circulation. 1999; 100: 1268-1273
        • Kartikasari A.E.
        • Georgiou N.A.
        • Visseren F.L.
        • et al.
        Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera.
        FASEB J. 2006; 20: 353-355
        • Jaffe E.A.
        • Nachman R.L.
        • Becker C.G.
        • Minick C.R.
        Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria.
        J Clin Invest. 1973; 52: 2745-2756
        • Mosmann T.
        Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.
        J Immunol Methods. 1983; 65: 55-63
        • Grootveld M.
        • Bell J.D.
        • Halliwell B.
        • Aruoma O.I.
        • Bomford A.
        • Sadler P.J.
        Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy.
        J Biol Chem. 1989; 264: 4417-4422
        • Sakariassen K.S.
        • Aarts P.A.
        • de Groot P.G.
        • Houdijk W.P.
        • Sixma J.J.
        A perfusion chamber developed to investigate platelet interaction in flowing blood with human vessel wall cells, their extracellular matrix, and purified components.
        J Lab Clin Med. 1983; 102: 522-535
        • van Zanten H.G.
        • Saelman E.U.
        • Schut-Hese K.M.
        • et al.
        Platelet adhesion to collagen type IV under flow conditions.
        Blood. 1996; 88: 3862-3871
        • Kartikasari A.E.
        • Georgiou N.A.
        • de Geest M.
        • et al.
        Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infection.
        Eur J Clin Invest. 2006; 36: 743-752
        • Saccani A.
        • Saccani S.
        • Orlando S.
        • et al.
        Redox regulation of chemokine receptor expression.
        Proc Natl Acad Sci USA. 2000; 97: 2761-2766
        • Kartikasari A.E.
        • Georgiou N.A.
        • Visseren F.L.
        • et al.
        Intracellular labile iron modulates adhesion of human monocytes to human endothelial cells.
        Arterioscler Thromb Vasc Biol. 2004; 24: 2257-2262
        • Zhang W.J.
        • Frei B.
        Intracellular metal ion chelators inhibit TNFalpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells.
        Free Radic Biol Med. 2003; 34: 674-682
        • Weber K.S.
        • von Hundelshausen P.
        • Clark-Lewis I.
        • Weber P.C.
        • Weber C.
        Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow.
        Eur J Immunol. 1999; 29: 700-712
        • Ulfman L.H.
        • Alblas J.
        • van Aalst C.W.
        • Zwaginga J.J.
        • Koenderman L.
        Differences in potency of CXC chemokine ligand 8-, CC chemokine ligand 11-, and C5a-induced modulation of integrin function on human eosinophils.
        J Immunol. 2005; 175: 6092-6099
        • Le Lan C.
        • Loreal O.
        • Cohen T.
        • et al.
        Redox active plasma iron in C282Y/C282Y hemochromatosis.
        Blood. 2005;
        • Ahmed N.K.
        • Hanna M.
        • Wang W.
        Nontransferrin-bound serum iron in thalassemia and sickle cell patients.
        Int J Biochem. 1986; 18: 953-956
        • Kooistra M.P.
        • Kersting S.
        • Gosriwatana I.
        • et al.
        Nontransferrin-bound iron in the plasma of haemodialysis patients after intravenous iron saccharate infusion.
        Eur J Clin Invest. 2002; 32: 36-41
        • Kohgo Y.
        • Ikuta K.
        • Ohtake T.
        • Torimoto Y.
        • Kato J.
        Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance.
        World J Gastroenterol. 2007; 13: 4699-4706
        • Chen X.L.
        • Zhang Q.
        • Zhao R.
        • Medford R.M.
        Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase.
        Am J Physiol Heart Circ Physiol. 2004; 286: H1001-H1007