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

Qian Li; Zhengli Yang; Peng Zhang; Yifan Zhao; Xinchun Yu; Peng Xue; Yiming Shao; Qiang Li; Xiaodong Jia; Qi Zhang; Longzhen Cheng; Miao He; Zhijun Zhou; Yubin Zhang

doi:10.1016/j.toxlet.2018.05.037

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

Toxicol Lett. 2018 Oct 1:295:54-63. doi: 10.1016/j.toxlet.2018.05.037. Epub 2018 May 31.

Authors

Qian Li¹, Zhengli Yang¹, Peng Zhang², Yifan Zhao¹, Xinchun Yu¹, Peng Xue¹, Yiming Shao¹, Qiang Li³, Xiaodong Jia⁴, Qi Zhang⁵, Longzhen Cheng⁵, Miao He⁵, Zhijun Zhou¹, Yubin Zhang⁶

Affiliations

¹ School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China.
² Huzhou Center for Disease Control and Prevention, Zhejiang 313000, China.
³ School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China; Putuo District Center for Disease Control and Prevention, Shanghai 200333, China.
⁴ Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China.
⁵ State Key Laboratory of Medical Neurobiology, Institutes of Brain Sciences, Fudan University, Shanghai 200032, China.
⁶ School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China. Electronic address: yz001@fudan.edu.cn.

PMID: 29859861
DOI: 10.1016/j.toxlet.2018.05.037

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-2^s) and DBA/2 mice (H-2^d) 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.

Keywords: Bone marrow-resident macrophages; Hematopoietic stem cells; IFNγ; Mercury chloride; Methyl mercury.

Publication types

Comparative Study

MeSH terms

Animals
Cell Communication / drug effects*
Cell Proliferation / drug effects*
Cells, Cultured
Coculture Techniques
Dose-Response Relationship, Drug
Hematopoietic Stem Cells / drug effects*
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / pathology
Interferon-gamma / metabolism*
Macrophages / drug effects*
Macrophages / metabolism
Macrophages / pathology
Mercuric Chloride / toxicity*
Methylmercury Compounds / toxicity
Mice, Inbred DBA
Signal Transduction / drug effects

Substances

IFNG protein, mouse
Methylmercury Compounds
Mercuric Chloride
Interferon-gamma