Toxicology Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Harwell Campus, OX11 0RQ, UK.
Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
Paraquat (PQ) is a redox cycling herbicide known for its acute toxicity in humans. Airway parenchymal cells have been identified as primary sites for PQ accumulation, tissue inflammation and cellular injury. However, the role of immune cells in PQ induced tissue injury is largely unknown. To explore this further, primary cultures of human CD34+ stem cell derived macrophages (MC) and dendritic cells (DC) were established and characterised using RNA-Seq profiling. The impact of PQ on DC and MC cytotoxicity revealed increased effect within DC cultures. PQ toxicity mechanisms were examined using sub-cytotoxic concentrations and TempO-seq transcriptomic assays. Comparable increases for several stress response pathway (NFE2L2, NF-kB and HSF) dependent genes were observed across both cell types. Interestingly, PQ induced unfolded protein response (UPR), p53, Irf and DC maturation genes in DC but not in MC. Further exploration of the immune modifying potential of PQ was performed using the common allergen house dust mite (HD). Co-treatment of PQ and HD resulted in enhanced inflammatory responses within MC but not DC. These results demonstrate immune cell type differential responses to PQ, that may underlie aspects of acute toxicity and susceptibility to inflammatory disease.
百草枯（PQ）是一种氧化还原循环除草剂，已知对人体具有急性毒性。气道实质细胞已被确定为 PQ 蓄积、组织炎症和细胞损伤的主要部位。然而，免疫细胞在 PQ 诱导的组织损伤中的作用在很大程度上尚不清楚。为了进一步探讨这一问题，建立了人 CD34+干细胞衍生的巨噬细胞（MC）和树突状细胞（DC）的原代培养物，并通过 RNA-Seq 分析进行了表征。用 PQ 处理 DC 和 MC 细胞，发现 DC 中的细胞毒性作用增加。使用亚细胞毒性浓度和 TempO-seq 转录组学测定研究了 PQ 的毒性机制。在两种细胞类型中，几种应激反应途径（NFE2L2、NF-kB 和 HSF）相关基因均观察到类似的增加。有趣的是，PQ 诱导 DC 中未折叠蛋白反应（UPR）、p53、Irf 和 DC 成熟基因，但在 MC 中未诱导。进一步研究了 PQ 对常见过敏原屋尘螨（HD）的免疫调节潜力。PQ 和 HD 共同处理导致 MC 中的炎症反应增强，但 DC 中没有。这些结果表明免疫细胞对 PQ 的反应存在差异，这可能是急性毒性和易患炎症性疾病的基础。
