CircEpc1 Promotes Ricin Toxin-Induced Inflammation via Activation of NF-κB and MAPK Signaling Pathways by Sponging miR-5114.

Mingxin Dong,Kaikai Yu,Jianxu Zhang,Wensen Liu,Xiaohao Zhang,Guiru Zhao,Chengbiao Sun,Ying Chang,Na Zhao,Guangchao Sun,Na Xu,Haotian Yu,Yan Wang

doi:10.3389/fphar.2021.767900

Abstract

Increasing studies have concentrated on investigating circular RNAs (circRNAs) as pivotal regulators in the progression of numerous diseases and biological processes and abundant evidence shows that circRNAs are participated in the regulation of innate immune responses. Several studies showed that Ricin Toxin (RT) could induce inflammatory injury. There was no research on the particular functions and underlying mechanisms of circRNAs in RT-induced inflammation. In this study, RNA sequencing performed on RT-treated and normal RAW264.7 macrophage cells was used to investigated the differentially expressed circRNAs. Based on the dataset, the expression of circEpc1 (mmu_circ_0,000,842) was identified higher in RT-treated cells. Moreover, gain-and-loss function assays showed that circEpc1 function as a promoter in RT-induced inflammation in vivo and in vitro. Mechanistically, circEpc1 acted as a miR-5114 sponge to relieve the suppressive effect of miR-5114 on its target NOD2 and thereby activating NF-κB and MAPK signaling pathways. Our results illuminated a link between RT-induced inflammation and the circEpc1 regulatory loop and provided novel insight into the functions of circRNA in innate immune, which may emerge as a potential target in immunotherapy to control the RT-induced inflammatory injury.

Highlights

Ricin toxin (RT) is a natural plant toxin derived from the seeds of the castor plant (Ricinus communis), which is widely cultivated and processed worldwide (Audi et al, 2005)
To identify circRNAs that are crucial to Ricin Toxin (RT)-induced inflammation, RNA-seq was performed for RT-treated RAW264.7 macrophage cells and matched normal RAW264.7 macrophage cells
These results suggested that circEpc1 as an upregulated circRNA participate in RTinduced RAW264.7 macrophage inflammation

Summary

Introduction

Ricin toxin (RT) is a natural plant toxin derived from the seeds of the castor plant (Ricinus communis), which is widely cultivated and processed worldwide (Audi et al, 2005). The damage of the 28 S rRNA by RT triggers a specific kinase-activated pathway and induces inflammation (Sowa-Rogozinska et al, 2019). Based on our previous work, RT-treated macrophages release various types of cellular factors, including IL-6, TNF-α, IFN-β, and other circEpc Promotes Ricin Toxin-Induced Inflammation cytokines (Liao et al, 2016; Dong et al, 2020). When these cellular events occur, an intracellular signaling cascade is activated through various pattern-recognition receptors (PRRs) spoke on macrophages. Activation of NOD2 results in activation of multiple signaling pathways, such as NF-κB and MAPK pathways, and leads to types of inflammation responses

Methods

Results

Conclusion