Long noncoding RNA Nron and its functional motif modulate macrophage-mediated inflammatory response

INTRODUCTION: Non-resolving macrophage-mediated inflammation is closely linked to the pathogenesis of systemic inflammatory response syndrome. Despite years of clinical trials attempting to mitigate the harmful effects of excessive inflammation, these efforts have largely been unsuccessful. Therefore, it is essential to develop novel therapeutic strategies. OBJECTIVE: To explore the role of Nron in inflammatory diseases and evaluate the therapeutic effect. METHODS: Conditional knockout/knockin mice were used for a systematic evaluation of Nron function in lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-induced sepsis. Quantitative real-time PCR, western blot, luciferase reporter assay, and RNA-RNA interaction assay were performed to investigate mechanisms and identify functional motifs. An enhanced lipid nanoparticle (LNP) formulation was constructed for targeted macrophage delivery and therapy. Moreover, monocytes were obtained from blood of patients with sepsis for in vitro culture, and the serum for enzyme-linked immunosorbent assay (ELISA) detection. Data analysis was conducted using GraphPad Prism 8. RESULTS: Conditional knockout of Nron in myeloid cells exacerbates LPS or CLP-induced sepsis, while the conditional transgenic mice exhibited a survival advantage with alleviated tissue inflammation and damage. Nron enhances sirtuin 1 (SIRT1) deacetylase activity via sponging miR-146a-3p/miR-16-1-3p in macrophages, thus regulating on nuclear factor kappa B (NF-κB) signaling by inhibiting p65 acetylation/phosphorylation directly or via HIF-1 signaling. The conserved functional motif of Nron (NCM2) has a longer half-life and LNP-NCM2 targeted to macrophages effectively alleviated sepsis in mice. CONCLUSION: Nron serves as a crucial negative regulator of excessive inflammatory responses, and its functional motifs can be used as a potential therapeutic agent for inflammatory diseases such as sepsis.