College of Life Science, Yangtze University, Jingzhou, 434025, China.
National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University (HZAU), Wuhan, 430070, China.
Food Chem Toxicol. 2023 Sep;179:113975. doi: 10.1016/j.fct.2023.113975. Epub 2023 Jul 28.
Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.
真菌毒素脱氧雪腐镰刀烯醇（DON）通过损害宿主免疫系统和危害机体健康来负调控免疫反应。我们假设 DON 可以启动类似“免疫逃避”的主动免疫抑制机制，改变细胞微环境并逃避免疫监视。我们使用 RAW264.7 巨噬细胞模型来验证这一假设。DON 可快速增加免疫检查点 PD-1 和 PD-L1、炎症细胞因子 TGF-β以及关键免疫逃避因子 STAT3、VEGF 和 TLR-4 的表达，并导致细胞缺氧。重要的是，缺氧诱导因子-1α（HIF-1α）是 DON 诱导免疫抑制的关键调节因子。DON 处理后，HIF-1α在细胞质中积累，并逐渐转移到细胞核内。此外，DON 通过 STAT3 信号激活 HIF-1α，上调下游信号，包括 PD-1/PD-L1。在 DON 处理下，STAT3/HIF-1α 轴上调了免疫抑制 miR-210-3p、lncRNA PVT1、lncRNA H19 和 lncRNA HOTAIR。此外，DON 还损害了线粒体功能，引起自噬，并抑制了免疫防御。综上所述，DON 通过 STAT3 信号触发 RAW264.7 细胞内缺氧，并快速激活 HIF-1α，激活免疫逃避信号、miRNAs 和 lncRNAs，从而启动免疫逃避的关键环节。该研究为准确预防和治疗真菌毒素引起的免疫性疾病提供了进一步的线索。
