Lead Impairs the Development of Innate Lymphoid Cells by Impeding the Differentiation of Their Progenitors

Abstract

Lead (Pb) is a heavy metal toxic to the immune system, yet the influence of Pb on innate lymphoid cells (ILC) remains to be defined. In this study, we found that occupationally relevant level of Pb exposure impaired ILC development at the progenitor level by activating Janus Kinase1. C57BL/6 mice treated with 1250 ppm, but not 125 ppm Pb acetic via drinking water for 8 weeks had reduced number of mature ILC, which was not caused by increased apoptosis or suppressed proliferation. Conversely, Pb increased the number of innate lymphoid cell progenitors (ILCP) in the bone marrow. The discordant observation indicated that an obstruction of ILCP differentiation into mature ILC during Pb exposure existed. Pb directly acted on ILCP to suppress their proliferation, indicating that ILCP were less activated during Pb exposure. Reciprocal ILCP transplantation assay confirmed that Pb impeded the differentiation of ILCP into mature ILC, as ILCP gave rise to fewer mature ILC in Pb-treated recipients compared with control recipients. In vitro assays suggested that the obstruction of ILCP differentiation by Pb exposure was due to increased activation of Janus Kinase1. Thus, Pb impeded ILCP differentiation into mature ILC to result in an accumulation of ILCP in the bone marrow and the resultant decreased number of mature ILC in lymphoid and nonlymphoid tissues in mice. Moreover, by analyses of ILC and ILCP in peripheral blood mononuclear cells of human subjects occupationally exposed to Pb, we revealed that Pb might also impede the development of ILC in human.

The Impact of Sedentary Lifestyle, High-fat Diet, Tobacco Smoke, and Alcohol Intake on the Hematopoietic Stem Cell Niches

“… 158 Furthermore, long-term low-dose lead exposure in mice results in reduced bone density and trabecular bone. 158 Lead suppresses proliferation of HSCs 159 and myeloid and lymphoid differentiation 160 , 161 in mice. In contrast, human smokers have increased numbers of monocytes and granulocytes and comparable levels of lymphocytes to nonsmokers.…”

Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis

“…Mechanisms associated with these effects involve higher expressions of interferon regulatory factor-8 (IRF8), which blocks C/EBPα and modulates neutrophil differentiation [ 230 ]. Recent evidence shows that exposure to Pb at occupational levels can result in lower numbers of innate lymphoid cells (ILCs) in the blood of mice, with this effect being dependent on activation of Janus Kinase-1 leading to an inability of BM CLP progenitors to become mature and be delivered into the bloodstream [ 231 ]. CLPs differentiate into innate lymphoid cell-restricted progenitors via transcription factor ID2, which further differentiate into mature ILC 1, 2, and 3 [ 232 ].…”

Mercury Chloride Impacts on the Development of Erythrocytes and Megakaryocytes in Mice

“…Environmental pollutants can significantly impact hematopoiesis [ 17 , 18 ]. We previously reported that heavy metals in the living environment such as cadmium, lead, and Hg significantly influenced the function of HSCs and the committed progenitors, leading to aberrant myelopoiesis and/or lymphopoiesis [ 19 , 20 , 21 , 22 , 23 ]. In terms of Hg, we found that Hg 2+ impacted the proliferation of HSCs and critically relied on IFNγ-dependent on BM-resident macrophages (MΦ); Hg 2+ increased the number of progenitors for granulocytes and MΦ in the BM of B10.S mice [ 19 , 24 ].…”