College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China.
College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan Province, China.
Chemosphere. 2020 Jun;249:126464. doi: 10.1016/j.chemosphere.2020.126464. Epub 2020 Mar 10.
Mycotoxins are toxic metabolites produced by fungal species that occur frequently in cereals and animal forages throughout the world, posing a serious threat to humans and animals. Although some studies showed the immunotoxicity of mycotoxins, little research focused on the two-way effects of mycotoxins on immune response in vitro and vivo. Here, we explored the effects of deoxynivalenol (DON), one of the most widely distributed mycotoxins, on immune function of piglets and porcine alveolar macrophages (PAMs), and found it exhibited bidirectional immune effects due to different exposure doses. Our results revealed that low doses of DON increased the expressions of TNF-α and IL-6 in piglets and PAMs, promoted the chemotaxis and phagocytosis of PAMs and transformed macrophages to M1 phenotype (P < 0.05). Conversely, high doses of DON increased the expressions of TGF-β and IL-10 in piglets and PAMs, inhibited the chemotaxis and phagocytosis of PAMs and induced macrophages M2-type polarization (P < 0.05). Mechanistically, DON exposure significantly activated the TLR4/NFκB pathway at low doses and induced mitophagy-mediated mitochondrial dysfunction at high doses in vitro and vivo. TLR4 interference and mitophagy activator, CCCP, were used to further confirm their roles. Therefore, we concluded that DON exposure at low doses caused immunostimulation via activating TLR4/NFκB, whereas it was immunoinhibitory at high doses through blocking mitophagy. Our study suggested that both high and low doses mycotoxins contamination might be harmful, and further back up the necessity to take a vigilant attitude to minimize humans and animals intake of mycotoxins in the environment.
真菌毒素是真菌产生的有毒代谢物，在世界各地的谷物和动物饲料中经常出现，对人类和动物构成严重威胁。虽然一些研究表明真菌毒素具有免疫毒性，但很少有研究关注真菌毒素在体外和体内对免疫反应的双向影响。在这里，我们研究了脱氧雪腐镰刀菌烯醇（DON），一种分布最广泛的真菌毒素之一，对仔猪和猪肺泡巨噬细胞（PAMs）免疫功能的影响，发现由于暴露剂量不同，它表现出双向免疫作用。我们的结果表明，低剂量 DON 增加了仔猪和 PAMs 中 TNF-α 和 IL-6 的表达，促进了 PAMs 的趋化性和吞噬作用，并将巨噬细胞转化为 M1 表型（P<0.05）。相反，高剂量 DON 增加了仔猪和 PAMs 中 TGF-β 和 IL-10 的表达，抑制了 PAMs 的趋化性和吞噬作用，并诱导巨噬细胞 M2 型极化（P<0.05）。在机制上，DON 暴露在低剂量下显著激活 TLR4/NFκB 通路，在高剂量下诱导线粒体自噬介导的线粒体功能障碍，在体内和体外。使用 TLR4 干扰和自噬激活剂 CCCP 进一步证实了它们的作用。因此，我们得出结论，DON 暴露在低剂量下通过激活 TLR4/NFκB 引起免疫刺激，而在高剂量下通过阻断线粒体自噬引起免疫抑制。我们的研究表明，高剂量和低剂量真菌毒素污染都可能是有害的，并进一步支持了保持警惕的必要性，以尽量减少人类和动物在环境中摄入真菌毒素。
