Enhancement of Regnase-1 expression with stem loop?targeting antisense oligonucleotides alleviates inflammatory diseases
Enhancement of Regnase-1 expression with stem loop?targeting antisense oligonucleotides alleviates inflammatory diseases
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茎环靶向反义寡核苷酸增强Regnase-1表达可减轻炎症性疾病
DOI：
10.1126/scitranslmed.abo2137
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发表时间：
2022
影响因子：
17.1
通讯作者：
Takeuchi Osamu
中科院分区：
文献类型：
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作者：
Tse Ka Man;Vandenbon Alexis;Cui Xiaotong;Mino Takashi;Uehata Takuya;Yasuda Keiko;Sato Ayuko;Tsujimura Tohru;Hia Fabian;Yoshinaga Masanori;Kinoshita Makoto;Okuno Tatsusada;Takeuchi Osamu
Regnase-1是一种核糖核酸酶，通过识别3′非翻译区（3′ UTR）中的茎环（SL）结构降解参与免疫反应的信使RNA（mRNA），在限制炎症中发挥重要作用。Regnase-1的表达失调与小鼠和人的炎性和自身免疫性疾病的发病机制相关。在这里，我们开发了一种治疗策略，通过阻断Regnase-1的自我调节来抑制炎症反应，这是通过同时使用两种反义磷酸二酰胺吗啉代寡核苷酸（MO）来改变Regnase-1与其3′UTR中SL结构的结合来介导的。Regnase-1靶向MO不仅通过稳定mRNA来增强Regnase-1表达，而且还有效地降低巨噬细胞中由Regnase-1控制的多种促炎转录物的表达。Regnase-1靶向MO的肠内给药通过抑制炎症级联反应改善了急性呼吸窘迫综合征和慢性纤维化。此外，用Regnase-1靶向MO进行颅内治疗通过促进稳态小胶质细胞和调节性T细胞群的扩增来减弱实验性自身免疫性脑脊髓炎的发展。Regnase-1表达与多发性硬化患者的疾病严重程度呈负相关，靶向humanRegnase-1 SL结构的MO可有效减轻人类免疫细胞中细胞因子的产生。总的来说，MO介导的Regnase-1自我调节途径的破坏是增强Regnase-1丰度的潜在治疗策略，这反过来通过抑制炎症为治疗炎性疾病提供了治疗益处。
Regnase-1 is an ribonuclease that plays essential roles in restricting inflammation through degrading messenger RNAs (mRNAs) involved in immune reactions via the recognition of stem-loop (SL) structures in the 3′ untranslated regions (3′UTRs). Dysregulated expression of Regnase-1 is associated with the pathogenesis of inflammatory and autoimmune diseases in mice and humans. Here, we developed a therapeutic strategy to suppress inflammatory responses by blocking Regnase-1 self-regulation, which was mediated by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) to alter the binding of Regnase-1 toward the SL structures in its 3′UTR. Regnase-1–targeting MOs not only enhanced Regnase-1 expression by stabilizing mRNAs but also effectively reduced the expression of multiple proinflammatory transcripts that were controlled by Regnase-1 in macrophages. Intratracheal administration of Regnase-1–targeting MOs ameliorated acute respiratory distress syndrome and chronic fibrosis through suppression of inflammatory cascades. In addition, intracranial treatment with Regnase-1–targeting MOs attenuated the development of experimental autoimmune encephalomyelitis by promoting the expansion of homeostatic microglia and regulatory T cell populations. Regnase-1 expression was inversely correlated with disease severity in patients with multiple sclerosis, and MOs targeting humanRegnase-1SL structures were effective in mitigating cytokine production in human immune cells. Collectively, MO-mediated disruption of the Regnase-1 self-regulation pathway is a potential therapeutic strategy to enhance Regnase-1 abundance, which, in turn, provides therapeutic benefits for treating inflammatory diseases by suppressing inflammation.