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The miR-7/EGFR axis controls the epithelial cell immunomodulation and regeneration and orchestrates the pathology in inflammatory bowel disease
Journal of Advanced Research ( IF 10.7 ) Pub Date : 2023-04-23 , DOI: 10.1016/j.jare.2023.04.011
Juanjuan Zhao 1 , Mengmeng Guo 2 , Yaping Yan 2 , Ya Wang 2 , Xu Zhao 2 , Jing Yang 2 , Jing Chen 2 , Chao Chen 2 , Lin Tang 2 , Wenhuan Zeng 3 , Yiting Liu 3 , Ming Qin 2 , Ya Zhou 4 , Lin Xu 5
Affiliation  

Introduction

The epithelial immunomodulation and regeneration are intrinsic critical events against inflammatory bowel disease (IBD). MiR-7 is well documented as a promising regulator in the development of various diseases including inflammatory diseases.

Objectives

This study aimed to assess the effect of miR-7 in intestinal epithelial cells (IECs) in IBD.

Methods

MiR-7def mice were given dextran sulfate sodium (DSS) to induce enteritis model. The infiltration of inflammatory cells was measured by FCM and immunofluorescence assay. 5’deletion assay and EMSA assays were performed to study the regulatory mechanism of miR-7 expression in IECs. The inflammatory signals and the targets of miR-7 were analyzed by RNA-seq and FISH assay. IECs were isolated from miR-7def, miR-7oe and WT mice to identify the immunomodulation and regeneration capacity. IEC-specific miR-7 silencing expression vector was designed and administered by the tail vein into murine DSS-induced enteritis model to evaluate the pathological lesions of IBD.

Results

We found miR-7 deficiency improved the pathological lesions of DSS-induced murine enteritis model, accompanied by elevated proliferation and enhanced transduction of NF-κB/AKT/ERK signals in colonic IECs, as well as decreased local infiltration of inflammatory cells. MiR-7 was dominantly upregulated in colonic IECs in colitis. Moreover, the transcription of pre-miR-7a-1, orchestrated by transcription factor C/EBPα, was a main resource of mature miR-7 in IECs. As for the mechanism, EGFR, a miR-7 target gene, was downregulated in colonic IECs in colitis model and Crohn's disease patients. Furthermore, miR-7 also controlled the proliferation and inflammatory-cytokine secretion of IECs in response to inflammatory-signals through EGFR/NF-κB/AKT/ERK pathway. Finally, IEC-specific miR-7 silencing promoted the proliferation and transduction of NF-κB pathway in IECs and alleviated the pathological damage of colitis.

Conclusion

Our results present the unknown role of miR-7/EGFR axis in IEC immunomodulation and regeneration in IBD and might provide clues for the application of miRNA-based therapeutic strategies in colonic diseases.



中文翻译:

miR-7/EGFR 轴控制上皮细胞免疫调节和再生并协调炎症性肠病的病理学

介绍

上皮免疫调节和再生是对抗炎症性肠病 (IBD) 的内在关键事件。MiR-7 被充分证明是一种有前途的调节剂,可用于包括炎症性疾病在内的各种疾病的发展。

目标

本研究旨在评估 miR-7 对 IBD 肠上皮细胞 (IEC) 的影响。

方法

MiR-7 def小鼠给予葡聚糖硫酸钠(DSS)以诱导肠炎模型。通过FCM和免疫荧光测定法测量炎性细胞的浸润。进行5'缺失测定和EMSA测定以研究miR-7在IEC中表达的调节机制。通过 RNA-seq 和 FISH 分析分析炎症信号和 miR-7 的靶标。从 miR-7 def、miR-7 oe和 WT 小鼠中分离出 IEC ,以鉴定免疫调节和再生能力。设计IEC特异性miR-7沉默表达载体,通过尾静脉给药进入小鼠DSS诱导的肠炎模型,以评估IBD的病理损伤。

结果

我们发现 miR-7 缺陷改善了 DSS 诱导的小鼠肠炎模型的病理损伤,伴随着结肠 IEC 中 NF-κB/AKT/ERK 信号的增殖和增强转导,以及炎症细胞的局部浸润减少。MiR-7 在结肠炎的结肠 IEC 中显着上调。此外, pre-miR-7a-1的转录, 由转录因子 C/EBPα 协调,是 IEC 中成熟 miR-7 的主要资源。至于机制,在结肠炎模型和克罗恩病患者的结肠 IEC 中,miR-7 靶基因 EGFR 被下调。此外,miR-7 还通过 EGFR/NF-κB/AKT/ERK 通路控制 IEC 的增殖和炎症细胞因子分泌,以响应炎症信号。最后,IEC特异性miR-7沉默促进了IECs中NF-κB通路的增殖和转导,减轻了结肠炎的病理损伤。

结论

我们的研究结果展示了 miR-7/EGFR 轴在 IBD 的 IEC 免疫调节和再生中的未知作用,并可能为基于 miRNA 的治疗策略在结肠疾病中的应用提供线索。

更新日期:2023-04-23
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