Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.
Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
Front Immunol. 2021 Feb 23;11:620283. doi: 10.3389/fimmu.2020.620283. eCollection 2020.
Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.
载脂蛋白 A-I 模拟肽是具有两亲性α-螺旋结构的肽，其功能与载脂蛋白 A-I 相似。临床前和临床研究已经证明了载脂蛋白 A-I 模拟肽在多种与炎症过程相关的适应证中的安全性和有效性。在这项研究中，我们通过腺相关病毒（AAV-L37pA）评估了肝脏中长期表达 L37pA 对腺相关病毒编码干扰素-α（AAV-IFNα）的影响。肝脏中 IFNα 的长期表达会导致 AAV 给药后一个月发生致命性血液毒性。同时给予 AAV-L37pA 可预防致命毒性，因为 AAV 给药后一个月 IFNα 的表达减少。为了确定 L37pA 的作用机制，在 AAV 给药后 15 天进行了基因组和蛋白质组分析，此时单独给予 AAV-IFNα 和同时给予 AAV-IFNα 和 AAV-L37pA 的小鼠中观察到 IFNα 和干扰素刺激基因的水平相似。载脂蛋白 A-I 模拟肽 L37pA 与 IFNα 的共表达调节了 IFNα 的基因表达程序，导致影响病原体相关分子模式受体、树突状细胞、NK 细胞和 Th1 免疫反应的炎症途径显著减少。蛋白质组分析证实了 L37pA 活性对几种炎症途径的影响，并表明 LXR/RXR 和 PPPARα/γ 核受体的激活。因此，肝脏中 L37pA 的长期表达会诱导抗炎作用，从而沉默腺相关病毒介导的 IFNα 表达。
