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Enhancement of Regnase-1 expression with stem loop-targeting antisense oligonucleotides alleviates inflammatory diseases

Tse, Ka Man Carman 京都大学 DOI:10.14989/doctor.k24192

2022.09.26

概要

Post-transcriptional regulation of gene expression plays important roles in fine-tuning inflammatory responses by regulating the stability of cytokine transcripts. Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that restricts inflammations by degrading inflammation-related mRNAs through recognition of the stem-loop (SL) structural motifs at the 3’ untranslated regions (UTRs). Accumulating evidence suggest that reduced Regnase-1 level is associated with the pathogenesis of a number of inflammatory diseases, however, strategies aiming to specifically increase Regnase-1 availability is lacking.

The goal of this study is to develop a therapeutic means to augment Regnase-1 expression through the control of its mRNA expression, and blocking Regnase-1 self-regulation pathway comes into focus. To this end, screening of the Regnase-1 3’ UTR by luciferase assay allowed the identification of two SL motifs responsible for Regnase-1 self-regulation. Consistently, introduction of antisense phosphorodiamidate morpholino oligonucleotides (MOs) targeting the right-arm of the two SL structures abrogated the binding interaction between Regnase-1 and its mRNA, thereby increasing Regnase-1 mRNA stability and protein availability. Further in vitro analyses showed that the enhanced Regnase-1 abundance greatly reduced the expression of inflammatory transcripts targeted by this RNase, highlighting the potential usage of Regnase-1-targeting MOs (Reg1-MOs) in mitigating inflammation.

Encouraged by these findings, further experiments were performed to examine the therapeutic potentials of Reg1-MOs in vivo using mouse models. In a LPS-induced lung injury model, Reg1-MOs ameliorated the detrimental effects of LPS by limiting neutrophil entry to the lung through repressing the cytokine and chemokine expressions from the alveolar macrophages. In addition, in a chronic inflammation model where bleomycin was used to induce pulmonary fibrosis, repeated treatment of Reg1-MOs effectively decreased the fibrotic lesions in lungs collected from Reg1-MO group. Quantitative analyses of the lung tissue corroborated that Reg1-MO treatment decreased the level of transcripts involved in lung fibrosis development. Lastly, the experimental autoimmune encephalomyelitis (EAE) model, a mouse model of human multiple sclerosis (MS), was used to investigate if increased Regnase-1 availability is beneficial for the treatment of autoimmune diseases. Local treatment of Reg1-MOs resolved the EAE disease severity and demyelination, partly resulted from a decreased level of inflammatory transcripts in the central nervous system (CNS).

In summary, this study has deepened the understanding of the potential of Regnase-1 enhancing therapies in mitigating inflammations. The acquired evidence suggested that Reg1-MOs not only enhanced Regnase-1 availability, but also effectively reduced the expression of proinflammatory transcripts in both in vitro and in vivo systems. To the best of its knowledge, this is the first study showing that targeting the self-regulatory elements in the mRNA untranslated regions with antisense MOs could be beneficial to alter the mRNA stability and expression of target mRNAs.

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