Department of Cardiorespiratory Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China.
Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
Hum Vaccin Immunother. 2024 Dec 31;20(1):2319965. doi: 10.1080/21645515.2024.2319965. Epub 2024 Feb 26.
Mimotope, a kind of peptide vaccine, is developed to bind natural receptor and inhibit the downstream signaling. We have demonstrated that the vaccination of Tocilizumab mimotopes could alleviate the renal fibrosis by interfering with both IL-6 and ferroptosis signaling. However, the effect of the vaccination of Tocilizumab mimotopes on the fibroblast was not investigated in previous study. Thus, we sought to explore the changes in the fibroblast induced by the Tocilizumab mimotopes vaccination. Bleomycin instillation was performed to construct the pulmonary fibrosis model after the immunization of Tocilizumab mimotopes. Lung histological analysis showed that the Tocilizumab mimotopes could significantly reduce the maladaptive repairment and abnormal remodeling. Immunoblotting assay and fluorescence staining showed that Immunization with the Tocilizumab mimotopes reduces the accumulation of fibrosis-related proteins. High level of lipid peroxidation product was observed in the animal model, while the Tocilizumab mimotopes vaccination could reduce the generation of lipid peroxidation product. Mechanism analysis further showed that Nrf-2 signaling, but not GPX-4 and FSP-1 signaling, was upregulated, and reduced the lipid peroxidation. Our results revealed that in the BLM-induced pulmonary fibrosis, high level of lipid peroxidation product was significantly accumulation in the lung tissues, which might lead to the occurrence of ferroptosis. The IL-6 pathway block therapy could inhibit lipid peroxidation product generation in the lung tissues by upregulating the Nrf-2 signaling, and further alleviate the pulmonary fibrosis.
模拟表位是一种肽疫苗，旨在与天然受体结合并抑制下游信号。我们已经证明，Tocilizumab 模拟表位的接种可以通过干扰 IL-6 和铁死亡信号来减轻肾纤维化。然而，在之前的研究中，尚未研究 Tocilizumab 模拟表位接种对成纤维细胞的影响。因此，我们试图探讨 Tocilizumab 模拟表位接种诱导的成纤维细胞变化。在接种 Tocilizumab 模拟表位后进行博来霉素灌注以构建肺纤维化模型。肺组织学分析表明，Tocilizumab 模拟表位可显著减少适应性修复和异常重塑。免疫印迹分析和荧光染色表明，接种 Tocilizumab 模拟表位可减少纤维化相关蛋白的积累。在动物模型中观察到脂质过氧化产物水平升高，而 Tocilizumab 模拟表位接种可减少脂质过氧化产物的生成。机制分析进一步表明，Nrf-2 信号通路被上调，而 GPX-4 和 FSP-1 信号通路未被上调，并减少了脂质过氧化。我们的结果表明，在 BLM 诱导的肺纤维化中，肺组织中脂质过氧化产物水平显著升高，可能导致铁死亡的发生。IL-6 通路阻断治疗可通过上调 Nrf-2 信号通路抑制肺组织中脂质过氧化产物的产生，从而进一步减轻肺纤维化。
