1. Academic Validation
  2. Lead suppresses interferon γ to induce splenomegaly via modification on splenic endothelial cells and lymphoid tissue organizer cells in mice

Lead suppresses interferon γ to induce splenomegaly via modification on splenic endothelial cells and lymphoid tissue organizer cells in mice

  • Ecotoxicol Environ Saf. 2022 Oct 1;244:114046. doi: 10.1016/j.ecoenv.2022.114046.
Yue Zhai 1 Yifan Zhao 1 Yufan Zhang 1 Jinyi He 1 Mengke Tang 1 Yalin Liu 1 Guangrui Yang 1 Peng Xue 1 Ye Yao 1 Miao He 2 Yanyi Xu 1 Weidong Qu 1 Yubin Zhang 3
Affiliations

Affiliations

  • 1 School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China.
  • 2 State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
  • 3 School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China. Electronic address: yz001@fudan.edu.cn.
Abstract

Splenomegaly is a symptom characterized by the presence of an enlarged spleen. The impact of environmental factors on splenomegaly is largely unknown. In this study, C57BL/6 mice were treated with 125 ppm or 1250 ppm lead (Pb) via drinking water for 8 wk, and the process of splenomegaly was evaluated. Treatment with 1250 ppm Pb, but not 125 ppm Pb, caused splenomegaly, which was associated with increased capacity for erythrocyte clearance. Intriguingly, Pb-caused splenomegaly was independent of lymphoid tissue inducer (LTi) cells, which produce lymphotoxins α and β (LTα/β) to activate endothelial cells and LT organizer (LTo) cells and drive the development of spleen physiologically. A direct action of Pb on endothelial cells and LTo cells did not impact their proliferation. On the other hand, during steady state, a tonic level of interferon (IFN)γ acted on endothelial cells and LTo cells to suppress splenomegaly, as IFNγ receptor (IFNγR)-deficient mice had enlarged spleens relative to wild-type mice; during Pb exposure, splenic IFNγ production was suppressed, thus leading to a loss of the inhibitory effect of IFNγ on splenomegaly. Mechanically, Pb acted on splenic CD4+ T cells to suppress IFNγ production, which impaired the Janus kinase (JAK)1/ signal transducer and activator of transcription (STAT)1 signaling in endothelial cells and LTo cells; the weakened JAK1/STAT1 signaling resulted in the enhanced nuclear factor-κB (NF-κB) signaling in endothelial cells and LTo cells, which drove their proliferation and caused splenomegaly. The present study reveals a previously unrecognized mechanism for the immunotoxicity of Pb, which may extend our current understanding for Pb toxicology.

Keywords

Endothelial cells; Interferon γ/Jak1/STAT1; Lead; Lymphoid tissue organizer cells; NF-κB; Splenomegaly.

Figures
Products