Il-22 Ameliorates Dss-Induced Colitis Through the Upregulation of LncRNA-UCL to Accelerate Claudin-1 Expression via Sequestering miR-568 in Mice

Abstract

Background: Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease (IBD) closely associated with intestinal homeostasis dysregulation. At present, clinical treatment options for UC are highly limited. Interleukin-22 (IL-22) treatment is regarded as an effective therapeutic strategy for the treatment of UC. The abnormal expression of long noncoding RNAs (lncRNAs) has been detected in many inflammatory diseases, including UC. In this study, we aimed to investigate the function of IL-22 and the function of lncRNAs in the UC on dextran sulfate sodium (DSS)-induced colitis in mice. Methods: The mice were intraperitoneally injected with IL-22 or PBS and then DSS was used to induce colitis. The histopathological parameters of the mice were determined using histological and molecular detection approaches. Then, RNA-sequencing was performed to screen the differential lncRNAs expression profile compared with the control group, before and after IL-22 treatment of the mice. Quantitative real time PCR (qRT-PCR) and lentivirus identified lncRNA-Ulcerative Colitis LncRNA (lncRNA-UCL) as the molecular regulator of the colitis mice. RNA-pulldown was performed to validate the interaction between lncRNA-UCL and mmu-miR-568. Meanwhile, claudin-1 was predicted and confirmed as the target molecule of mmu-miR-568 using dual luciferase assay. Findings: IL-22 treatment could significantly improve the histopathological features and decrease pro-inflammatory cytokine production in DSS-induced colitis mice by enhancing the expressions of tight and adherent junction proteins, and promoting the proliferation and suppressing the apoptosis of intestinal epithelial cells. LncRNA-UCL expression was significantly downregulated in DSS-induced colitis mice, while IL-22 treatment effectively reversed this effect. In terms of mechanism, lncRNA-UCL regulates intestinal epithelial homeostasis by sequestering mmu-miR-568 and maintaining the expression of the tight junction protein, claudin-1. Interpretation: Our results implied that IL-22 can alleviate symptoms of DSS-induced colitis via enhancing lncRNA-UCL expression by maintaining the expression levels of tight junction and adherent junction proteins. Therefore, the lncRNA/miR-568/claudin-1 axis plays a pivotal role in regulating intestinal epithelial cell homeostasis under the effect of IL-22. Funding: This study was supported by the National Natural Science Foundation of China (No. 81800489). We are grateful to the collaboration of all fellows at Department of Gastroenterology, Shenzhen People’s Hospital, Jinan University. Declaration of Interest: The authors have declared that no competing interest exists. Ethical Approval: All experiments performed on animals were approved by the Medical Ethics Committee of Shenzhen People’s Hospital, Shenzhen, China.