| 研究実績の概要 |
Regnase-1 is a negative regulator of inflammation. It restricts immune responses by limiting the stability of inflammatory mRNAs (Il6, Il1b, Regnase-1, etc) through recognition of stem-loop (SL) structures in 3'untranslated regions (UTRs). In this project, we aimed to develop a therapeutic strategy to suppress inflammations through manipulating Regnase-1 availability. We achieved this by modulating the binding interaction between Regnase-1 and its SL structures, which was enabled by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) targeting the right arms of the SL structure.
Blocking Regnase-1 self-regulation by MOs successfully enhanced Regnase-1 expression in macrophages, which in turn decreased the expression of inflammatory transcripts targeted by Regnase-1. In addition, we observed that tissue-targeted delivery of Regnase-1-targeting-MOs attenuated inflammation and immune cell infiltration to disease sites in mouse models of acute respiratory distress syndrome, bleomycin-induced pulmonary fibrosis, and experimental autoimmune encephalomyelitis. At last, we found that Regnase-1 expression was inversely correlated with the disease severity of patients with multiple sclerosis, whereas MO treatment against human Regnase-1 SL structures successfully blunted their expression of pro-inflammatory genes upon LPS stimulation. Overall, our findings highlight that MO-mediated enhancement of Regnase-1 expression could serve as a novel therapeutic strategy to restrict inflammation and improve disease outcomes in mouse and human.
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