Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice.
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-gamma-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-gamma and, hence, autoimmune responses.
Fagoonee
Sharmila
S
Department of Genetics, Biology and Biochemistry, and Molecular Biotechnology Center, University of Turin, Turin, Italy. sharmila.fagoonee@unito.it
Caorsi
Cristiana
C
Giovarelli
Mirella
M
Stoltenberg
Meredin
M
Silengo
Lorenzo
L
Altruda
Fiorella
F
Camussi
Giovanni
G
Tolosano
Emanuela
E
Bussolati
Benedetta
B
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006466:Hemopexin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D008627:Mercuric Chloride / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009928:Organ Specificity; D013154:Spleen / Q000187:drug effects
D016207:Cytokines; D008627:Mercuric Chloride; D006466:Hemopexin