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

Abstract

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-γ-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-γ and, hence, autoimmune responses.

Editorial: Hemopexin: newest member of the anti-inflammatory mediator club

“…At present, data to support or refute this notion are lacking. However, in contrast to what one might expect initially based on the results presented by Liang et al [12], the induction of autoimmune disease by chronic mercury exposure is suppressed in hemopexin KO mice [13]. However, the amelioration of mercuryinduced autoimmune disease in hemopexin KO mice appears to be related to iron overload in certain subpopulations of lymphocytes rather than down-regulation of the inflammatory response of macrophages exposed to microbial products.…”

“…However, the amelioration of mercuryinduced autoimmune disease in hemopexin KO mice appears to be related to iron overload in certain subpopulations of lymphocytes rather than down-regulation of the inflammatory response of macrophages exposed to microbial products. Thus, there is no discrepancy between the findings obtained by Liang et al [12] in their studies of the effects of hemopexin on cytokine secretion by LPS-stimulated macrophages and those obtained by Fagoonee et al [13] in their studies of autoimmune disease in hemopexin KO mice.…”

Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

“…In this article we have outlined the deleterious physiological consequences of IVH free heme and the role these effects play in the development and complications of various disease processes in humans. HPX's actions, biological roles, metabolism, and function have also been studied in rhesus monkeys, dogs, rabbits, rats, and HPX −/− mice (Tolosano et al, 1999 , 2002 ; Morello et al, 2007 ; Fagoonee et al, 2008 ; Vinchi et al, 2008 ; Li et al, 2009 ; Chen et al, 2011 ).…”

Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes

“…Additionally, other functions of Hx not clearly related to its role as an heme scavenger, have also been described thanks to the use of knock-out mice (Fagoonee et al, 2008; Spiller et al, 2011; Rolla et al, 2013). …”