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Lack of Plasma Protein Hemopexin Dampens Mercury-Induced Autoimmune Response in Mice¹

Sharmila Fagoonee^2,*, Cristiana Caorsi^,, Mirella Giovarelli^,, Meredin Stoltenberg^¶, Lorenzo Silengo^*, Fiorella Altruda^*, Giovanni Camussi^,, Emanuela Tolosano^3,* and Benedetta Bussolati^2,3,,

^* Department of Genetics, Biology and Biochemistry, and Molecular Biotechnology Center; Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy; Center for Experimental Research and Medical Studies; Department of Internal Medicine, San Giovanni Battista Hospital, Turin, Italy; and ^¶ Department of Neurobiology, Institute of Anatomy, University of Aarhus, Århus, Denmark

Several factors affect the autoimmune response, including iron-dependent modulation of T cells. Hemopexin is the plasma protein with the highest binding affinity to heme. It mediates heme-iron recovery in the liver, thus controlling heme-iron availability in peripheral cells. The aim of the present study was to investigate the role of hemopexin in the progress of an autoimmune response. To this end, we chose a mouse model of mercury-induced autoimmunity and evaluated the susceptibility of hemopexin-null mice to mercury treatment compared with wild-type controls. In this study we show that lack of hemopexin dampens mercury-induced autoimmune responses in mice. Hemopexin-null mice produced fewer antinuclear autoantibodies and had reduced deposits of immune complexes in the kidney after mercuric chloride treatment compared with wild-type mice. These features were associated with a reduction in activated T cells and lower absolute B cell number in spleen and impaired IgG1 and IgG2a production. In contrast, in hemopexin-null mice the response to OVA/CFA immunization was maintained. In addition, hemopexin-null mice had reduced transferrin receptor 1 expression in T cells, possibly due to the increase in heme-derived iron. Interestingly, CD4⁺T cells isolated from mercury-treated hemopexin-null mice show reduced IFN--dependent STAT1 phosphorylation compared with that of wild-type mice. Our data suggest that hemopexin, by controlling heme-iron availability in lymphocytes, modulates responsiveness to IFN- and, hence, autoimmune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Italian Ministry of University and Research to E.T. and F.A., and by Regione Piemonte to F.A. and B.B. (Grant A141). C.C. is supported by a fellowship from Fondazione Denegri.

² Address correspondence and reprint requests to Dr. Sharmila Fagoonee, University of Turin, Via Nizza 52, Turin, Italy. E-mail address: sharmila.fagoonee{at}unito.it or Dr. Benedetta Bussolati, Molecular Biotechnology Center, Via Nizza 52, 10126 Turin, Italy. E-mail address: benedetta.bussolati{at}unito.it

³ E.T. and B.B. contributed equally to this work.

⁴ Abbreviations used in this paper: HO, heme-oxygenase; ANA, antinuclear antibody; CO, carbon monoxide; HgCl₂, mercuric chloride; Hx-null, hemopexin-null; IC, immune complex; TfR1, transferrin receptor 1; Treg, T regulatory cell.