Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Oklahoma State University, Stillwater, OK, United States.
Front Immunol. 2023 Jul 5;14:1177624. doi: 10.3389/fimmu.2023.1177624. eCollection 2023.
A family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response, which may have therapeutic potential. We investigated immune response modulation by SLR10. We addressed whether RIG-I pathway activation with SLR10 leads to protection of nonsmoking (NS) and cigarette smoke (CS)-exposed mice after influenza A virus (IAV) infection.
Mice were given 25 µg of SLR10 1 day before IAV infection. We compared the survival rates and host immune responses of NS and CS-exposed mice following challenge with IAV.
SLR10 significantly decreased weight loss and increased survival rates in both NS and CS-exposed mice during IAV infection. SLR10 administration repaired the impaired proinflammatory response in CS-exposed mice without causing more lung injury in NS mice as assessed by physiologic measurements. Although histopathologic study revealed that SLR10 administration was likely to result in higher pathological scores than untreated groups in both NS and CS mice, this change was not enough to increase lung injury evaluated by lung-to-body weight ratio. Both qRT-PCR on lung tissues and multiplex immunoassay on bronchoalveolar lavage fluids (BALFs) showed that most IFNs and proinflammatory cytokines were expressed at lower levels in SLR10-treated NS mice than control-treaded NS mice at day 5 post infection (p.i.). Remarkably, proinflammatory cytokines IL-6, IL-12, and GM-CSF were increased in CS-exposed mice by SLR10 at day 5 p.i. Significantly, SLR10 elevated the ratio of the two chemokines (CXCL9 and CCL17) in BALFs, suggesting macrophages were polarized to classically activated (M1) status. testing also found that SLR10 not only stimulated human alveolar macrophage polarization to an M1 phenotype, but also reversed cigarette smoke extract (CSE)-induced M2 to M1 polarization.
Our data show that SLR10 administration in mice is protective for both NS and CS-exposed IAV-infected mice. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection. The protective effects by SLR10 may be a promising intervention for therapy for infections with viruses, particularly those with CS-enhanced susceptibility to adverse outcomes.
设计了一组短的合成、三磷酸化茎环 RNA（SLRs）家族，以激活视黄酸诱导基因 I（RIG-I）途径并诱导强烈的干扰素（IFN）反应，这可能具有治疗潜力。我们研究了 SLR10 对免疫反应的调节作用。我们探讨了用 SLR10 激活 RIG-I 途径是否会导致非吸烟（NS）和吸烟暴露（CS）的小鼠在感染甲型流感病毒（IAV）后得到保护。
在感染 IAV 前一天，给小鼠给予 25 µg SLR10。我们比较了 NS 和 CS 暴露的小鼠在感染 IAV 后的存活率和宿主免疫反应。
SLR10 显著降低了 NS 和 CS 暴露的小鼠在感染 IAV 期间的体重减轻和提高了生存率。SLR10 的给药修复了 CS 暴露的小鼠中受损的促炎反应，而在 NS 小鼠中没有导致更高的肺损伤，这是通过生理测量评估的。尽管组织病理学研究表明，SLR10 给药在 NS 和 CS 小鼠中可能导致更高的病理评分，而不是未处理的组，但这种变化不足以增加通过肺与体重比评估的肺损伤。肺部组织的 qRT-PCR 和支气管肺泡灌洗液（BALF）的多重免疫测定均显示，在感染后第 5 天（p.i.），SLR10 处理的 NS 小鼠中大多数 IFNs 和促炎细胞因子的表达水平均低于对照处理的 NS 小鼠。值得注意的是，SLR10 在感染后第 5 天增加了 CS 暴露的小鼠中促炎细胞因子 IL-6、IL-12 和 GM-CSF 的水平。重要的是，SLR10 升高了 BALF 中两种趋化因子（CXCL9 和 CCL17）的比值，提示巨噬细胞极化到经典激活（M1）状态。功能测试还发现，SLR10 不仅刺激人肺泡巨噬细胞向 M1 表型极化，而且逆转了香烟烟雾提取物（CSE）诱导的 M2 向 M1 极化。
我们的数据表明，SLR10 给药对 NS 和 CS 暴露的 IAV 感染小鼠均具有保护作用。从机制上讲，SLR10 治疗在流感感染期间促进了肺部的 M1 巨噬细胞极化。SLR10 的保护作用可能是治疗病毒感染的一种有前途的干预措施，特别是对 CS 增强不良结局易感性的病毒感染。
