Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou 550025, China.
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou 550025, China.
Toxicol Appl Pharmacol. 2021 Jan 1;410:115364. doi: 10.1016/j.taap.2020.115364. Epub 2020 Dec 5.
Semaphorin (Sema) 3A and Sema 4A are immunomodulatory molecules with a common receptor, neuropilin-1 (NRP-1), on the immune cells. Sema 3A binds to NRP-1 and inhibits T cell activation and inflammation, while Sema 4A binds to NRP-1 and promotes T cell activation and inflammation. These molecules are associated closely with the regulation of protein kinase B (AKT)/nuclear factor-kappaB (NF-κB) signaling, which are poorly understood in arsenic toxicity. The present study explored the role of Sema 3A or Sema 4A in arsenic-induced hepatotoxicity in mice. Arsenic exposure induced hepatic injury and resulted in the activations of p-AKT2, NF-κB p65, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, downregulation of Sema 3A, and upregulation of Sema 4A or NRP-1. Interestingly, intervention with anti-Sema 4A antibody showed the mitigation of arsenic-induced hepatotoxicity, accompanied by the downregulation of Sema 4A, rebound of Sema 3A, and upregulation of NRP-1. And, the inflammatory signaling p-AKT2 or NF-κB p65, and NLRP3 inflammasome showed a downregulation compared with arsenic treatment group. In contrast, anti-Sema 3A antibody intervention did not show the significant effect in the histopathological features compared with arsenic treatment group. In conclusion, the anti-Sema 4A antibody antagonizes arsenic-induced hepatotoxicity in mice and may be involved in the inhibitions of AKT2/NF-κB and NLRP3 inflammatory signaling mediated synergistically by Sema 4A or Sema 3A and their receptor NRP-1.
信号素（Sema）3A 和 Sema 4A 是具有免疫细胞上共同受体神经纤毛蛋白-1（NRP-1）的免疫调节分子。Sema 3A 与 NRP-1 结合，抑制 T 细胞激活和炎症，而 Sema 4A 与 NRP-1 结合，促进 T 细胞激活和炎症。这些分子与蛋白激酶 B（AKT）/核因子-κB（NF-κB）信号通路的调节密切相关，而砷毒性对其知之甚少。本研究探讨了 Sema 3A 或 Sema 4A 在小鼠砷诱导肝毒性中的作用。砷暴露诱导肝损伤，并导致 p-AKT2、NF-κB p65 和 NOD 样受体家族吡喃结构域包含 3（NLRP3）炎性小体的激活，Sema 3A 的下调，以及 Sema 4A 或 NRP-1 的上调。有趣的是，抗 Sema 4A 抗体干预显示出减轻砷诱导的肝毒性，伴随着 Sema 4A 的下调，Sema 3A 的反弹和 NRP-1 的上调。并且，炎性信号 p-AKT2 或 NF-κB p65 和 NLRP3 炎性小体的表达与砷处理组相比呈下调趋势。相比之下，与砷处理组相比，抗 Sema 3A 抗体干预在组织病理学特征方面没有显示出显著效果。总之，抗 Sema 4A 抗体拮抗小鼠砷诱导的肝毒性，可能与 Sema 4A 或 Sema 3A 及其受体 NRP-1 协同抑制 AKT2/NF-κB 和 NLRP3 炎症信号有关。
