Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
Mol Ther. 2022 Jun 1;30(6):2210-2223. doi: 10.1016/j.ymthe.2022.02.019. Epub 2022 Feb 18.
Microglial activation followed by recruitment of blood-borne macrophages into the central nervous system (CNS) aggravates neuroinflammation. Specifically, in multiple sclerosis (MS) as well as in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, activated microglia and macrophages (Mg/Mφ) promote proinflammatory responses and expand demyelination in the CNS. However, a potent therapeutic approach through the systemic route for regulating their functions has not yet been developed. Here, we demonstrate that a systemically injected DNA/RNA heteroduplex oligonucleotide (HDO), composed of an antisense oligonucleotide (ASO) and its complementary RNA, conjugated to cholesterol (Chol-HDO) distributed more efficiently to demyelinating lesions of the spinal cord in EAE mice with significant gene silencing than the parent ASO. Importantly, systemic administration of Cd40-targeting Chol-HDO improved clinical signs of EAE with significant downregulation of Cd40 in Mg/Mφ. Furthermore, we successfully identify that macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of Chol-HDO by Mg/Mφ of EAE mice. Overall, our findings demonstrate the therapeutic potency of systemically administered Chol-HDO to regulate activated Mg/Mφ in neuroinflammation.
小胶质细胞的激活，随后血液来源的巨噬细胞募集到中枢神经系统（CNS），加重神经炎症。具体来说，在多发性硬化症（MS）以及实验性自身免疫性脑脊髓炎（EAE），一种 MS 的啮齿动物模型中，活化的小胶质细胞和巨噬细胞（Mg/Mφ）促进促炎反应，并在中枢神经系统中扩大脱髓鞘。然而，通过系统途径调节其功能的有效治疗方法尚未开发。在这里，我们证明了一种系统注射的 DNA/RNA 异源双链寡核苷酸（HDO），由反义寡核苷酸（ASO）与其互补 RNA 组成，并与胆固醇（Chol-HDO）缀合，在 EAE 小鼠的脊髓脱髓鞘病变中分布更有效，具有显著的基因沉默，比母体 ASO 更有效。重要的是，靶向 CD40 的 Chol-HDO 的系统给药改善了 EAE 的临床症状，并在 Mg/Mφ 中显著下调了 CD40。此外，我们成功地鉴定出巨噬细胞清道夫受体 1（MSR1）是 Chol-HDO 被 EAE 小鼠的 Mg/Mφ 摄取的原因。总体而言，我们的研究结果表明，系统给予 Chol-HDO 具有调节神经炎症中活化的 Mg/Mφ 的治疗潜力。
