Lead in synergism with IFNc acts on bone marrow-resident macrophages to increase the quiescence of hematopoietic stem cells

Abstract

Lead (Pb) is a highly toxic heavy metal that broadly exists in our living environment. Although Pb has been shown to influence the development of immune cells, to date, the impact of Pb on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains unknown. As people are ubiquitously exposed to Pb and HSC are essential for human health, understanding the impact of Pb on HSC is significant for public health. In this study, we found that wild-type B6 mice treated with 1250 ppm Pb, but not 125 ppm Pb via drinking water for 8 weeks had increased quiescence of HSC in the BM. Functional analyses demonstrated that wild-type mice treated with 1250 ppm Pb had increased potential for HSC to repopulate the immune system and engraft to the niche in the BM under a competitive chimeric microenvironment of lethally irradiated recipients. Moreover, we found that Pb-increased quiescence of HSC critically relied on a synergetic action of Pb and interferon c (IFNc) on BM-resident macrophages (BM-MU), but not a direct action of Pb on HSC. Specifically, in steady state, BM-MU promoted HSC proliferation; and upon Pb treatment, IFNc was induced in the BM, and thereafter Pb in synergism with IFNc acted on BM-MU to cause BM-MU to become suppressive for HSC proliferation, thus leading to increased quiescence of HSC. Our study suggests that Pb increased the quiescence of HSC via a synergetic action of Pb and IFNc on BM-MU, which was previously unrecognized toxicity of Pb.