Mercury impact on hematopoietic stem cells is regulated by IFNγ-dependent bone marrow-resident macrophages in mice

Abstract

Although immunotoxic effects of mercury (Hg) have been extensively investigated, the influence of Hg on hematopoietic stem cells (HSC) remains elusive. The aim of this study was to investigate the effects of Hg on HSC. B10.S (H-2s) and DBA/2 mice (H-2d) were treated with Hg chloride (25, 50 or 100 μM HgCl2) or methyl Hg (1.25, 3.75 or 6.25 μM MeHg) via drinking water for 4 weeks, and thereafter, HSC in the bone marrow (BM) were evaluated. The number of HSC in B10.S mice was increased after treatment with 50 μM HgCl2 and decreased after treatment with 100 μM HgCl2; the number of HSC in DBA/2 mice was reduced after treatment with 50 μM HgCl2 and unaffected after treatment with 25 μM HgCl2. These effects from the HgCl2 treatments were associated with alterations of HSC proliferation, IFNγ expression and BM-resident macrophages. In vivo neutralization of IFNγ diminished the HgCl2-driven HSC proliferation, and in vivo replenishment of recombinant IFNγ eliminated the HgCl2 suppression of HSC proliferation and allowed HgCl2 enhancement of proliferation, suggesting a pivotal role of IFNγ in HSC proliferation regulated by HgCl2. In vivo depletion of macrophages and an in vitro co-culture assay indicated that BM-resident macrophages promoted HSC proliferation during HgCl2 exposure. Furthermore, the induction of BM-resident macrophages was critically dependent on IFNγ. In contrast, MeHg did not influence HSC in B10.S or DBA/2 mice. Collectively, HgCl2, but not MeHg, affects HSC through regulating IFNγ-dependent BM-resident macrophages in mice. These findings reveal a previously unknown toxicity of Hg.