LAUSR

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 human Regnase-1 SL 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. Description Enhancing Regnase-1 expression promotes an anti-inflammatory state and is a potential strategy against inflammatory diseases. A Regnase-1 remedy Regnase-1 is an RNase known to limit inflammation by targeting specific mRNAs through recognition of stem-loop (SL) structures in 3′ untranslated regions. Tse et al. now describe a therapeutic approach of blocking Regnase-1 self-regulation to limit inflammatory responses. They targeted the binding interaction between Regnase-1 and SL structures using two antisense phosphorodiamidate morpholino oligonucleotides (MOs), which enhanced Regnase-1 expression in macrophages and, in turn, reduced expression of proinflammatory transcripts targeted by this RNase. Tissue-targeted delivery of Regnase-1–specific MOs attenuated acute respiratory inflammation and chronic fibrosis in the lung and experimental autoimmune encephalitis symptoms in the nervous system. Regnase-1 expression also inversely correlated with multiple sclerosis disease severity in patients. These findings highlight a role for Regnase-1 in inflammatory diseases and suggest potential therapeutic benefits of targeting this mechanism.