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Targeting a novel hsa_circ_0000520/miR-556-5p/NLRP3 pathway-mediated cell pyroptosis and inflammation attenuates ovalbumin (OVA)-induced allergic rhinitis (AR) in mice models
Inflammation Research ( IF 6.7 ) Pub Date : 2021-05-24 , DOI: 10.1007/s00011-021-01472-z
Xiaofeng Yu 1 , Meng Wang 1 , He Zhao 1 , Zhiwei Cao 1
Affiliation  

Objectives

The circRNAs–miRNAs–mRNAs competing endogenous RNA (ceRNA) networks involve in regulating the development of various inflammation-associated diseases, including allergic rhinitis (AR), and the present study aimed to identify novel AR-associated ceRNA networks.

Methods

The mRNA and protein levels of the associated genes were, respectively, examined by real-time qPCR and western blot analysis. The targeting sites in miR-556-5p and NLRP3 were validated by performing dual-luciferase reporter gene system assay. ELISA was used to measure inflammatory cytokines secretion, and CCK-8 assay was conducted to determine cell proliferation.

Results

Here, we first identified a hsa_circ_0000520/miR-556-5p/NLRP3 signaling cascade triggered epithelium pyroptosis and inflammation to regulate the development of AR in cellular and mice models. Specifically, the pyroptosis-associated biomarkers (NLRP3, ASC, IL-1β and IL-18) and pro-inflammatory cytokines (OVA-specific IgE, TNF-α, IL-4 and IL-5) were upregulated in the nasal subjects collected from AR patients and ovalbumin (OVA)-induced AR mice models, compared to their normal counterparts. Next, using the ceRNA networks analysis software, we screened out a hsa_circ_0000520/miR-556-5p axis that potentially regulated NLRP3 in the human nasal epithelial cell line. Mechanistically, miR-556-5p targeted both hsa_circ_0000520 and 3′ untranslated region (3′UTR) of NLRP3, and knock-down of hsa_circ_0000520 inactivated NLRP3-mediated epithelium pyroptosis through miR-556-5p in a ceRNA-dependent manner. Furthermore, we proved that both hsa_circ_0000520 ablation and miR-556-5p overexpression suppressed NLRP3-mediated cell pyroptosis to attenuate AR in mice models.

Conclusions

Taken together, we evidenced that targeting the hsa_circ_0000520/miR-556-5p/NLRP3 signaling pathway was a novel AQ1strategy to ameliorate AR progression; however, future clinical data are still required to validate our preliminary results.



中文翻译:

靶向新型 hsa_circ_0000520/miR-556-5p/NLRP3 通路介导的细胞焦亡和炎症减轻小鼠模型中卵清蛋白 (OVA) 诱导的过敏性鼻炎 (AR)

目标

circRNAs-miRNAs-mRNAs 竞争内源性 RNA (ceRNA) 网络参与调节各种炎症相关疾病的发展,包括过敏性鼻炎 (AR),本研究旨在鉴定新的 AR 相关 ceRNA 网络。

方法

相关基因的 mRNA 和蛋白质水平分别通过实时 qPCR 和蛋白质印迹分析进行检查。miR-556-5p 和 NLRP3 中的靶向位点通过双荧光素酶报告基因系统测定进行验证。ELISA用于测量炎性细胞因子的分泌,并进行CCK-8测定以确定细胞增殖。

结果

在这里,我们首先确定了 hsa_circ_0000520/miR-556-5p/NLRP3 信号级联触发上皮细胞焦亡和炎症,以调节细胞和小鼠模型中 AR 的发展。具体而言,焦亡相关生物标志物(NLRP3、ASC、IL-1β 和 IL-18)和促炎细胞因子(OVA 特异性 IgE、TNF-α、IL-4 和 IL-5)在收集的鼻腔受试者中上调来自 AR 患者和卵清蛋白 (OVA) 诱导的 AR 小鼠模型,与其正常对应物相比。接下来,我们使用 ceRNA 网络分析软件筛选出一个 hsa_circ_0000520/miR-556-5p 轴,它可能在人鼻上皮细胞系中调节 NLRP3。从机制上讲,miR-556-5p 同时靶向 NLRP3 的 hsa_circ_0000520 和 3' 非翻译区(3'UTR),hsa_circ_0000520 的敲低通过 miR-556-5p 以依赖于 ceRNA 的方式灭活了 NLRP3 介导的上皮细胞焦亡。此外,我们证明 hsa_circ_0000520 消融和 miR-556-5p 过表达都抑制了 NLRP3 介导的细胞焦亡,从而减弱了小鼠模型中的 AR。

结论

总之,我们证明靶向 hsa_circ_0000520/miR-556-5p/NLRP3 信号通路是一种改善 AR 进展的新型 AQ1 策略;然而,仍需要未来的临床数据来验证我们的初步结果。

更新日期:2021-05-25
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