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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

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Abstract

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.

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Data availability

All the data had been included in the manuscript, and the original data could be obtained from the corresponding author upon reasonable request.

Abbreviations

AR:

Allergic rhinitis

OVA:

Ovalbumin

ceRNA:

Competing endogenous RNA

3′UTR:

3′ Untranslated region

NLRP3:

NLR family pyrin domain containing 3

Ox-LDL:

Oxidative low-density lipoprotein

HUVECs:

Human umbilical vein endothelial cells

CircRNA:

Circular RNA

miRNA:

MicroRNA

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Funding

This study was financially supported by Shengjing Hospital of China Medical University.

Author information

Authors and Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Sanhao Street No. 36, Shenyang, 110004, China

    Xiaofeng Yu, Meng Wang, He Zhao & Zhiwei Cao

Authors
  1. Xiaofeng Yu
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  2. Meng Wang
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  3. He Zhao
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  4. Zhiwei Cao
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Contributions

XY conducted most of the experiments, and was responsible for conception and manuscript drafting. MW and HZ provided technical support, and they helped to collect and analyze the data. ZC was the corresponding author who provided guidance for this work. Also, ZC proofread the manuscript and acquired funding to financially support this work.

Corresponding author

Correspondence to Zhiwei Cao.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All the clinical experiments were conducted in accordance with the Declaration of Helsinki, and were approved by the Ethics Committee of the Shengjing Hospital of China Medical University. Also, all the participants had signed the informed consent forms. In addition, all the animal experiments were approved by the Ethics Committee of of the Shengjing Hospital of China Medical University.

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All the co-authors agreed to publish the final version of this manuscript.

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Responsible Editor: John Di Battista.

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Supplementary Information

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Figure S1.

The (A) hsa_circ_0000520 overexpression vectors, (B) miR-556-5p mimic and inhibitor were transfected into RPMI2650 cells, respectively. **P < 0.01. (JPG 213 KB)

Figure S2.

The (A) hsa_circ_0000520 overexpression vectors, (B) miR-556-5p mimic and inhibitor were delivered into AR mice models, respectively. **P < 0.01. (JPG 230 KB)

11_2021_1472_MOESM3_ESM.jpg

Figure S3. Real-Time qPCR was performed to examine IL-4 and IL-5 mRNA levels in the mice nasal mucosal tissues. *P < 0.05. (JPG 127 KB)

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Yu, X., Wang, M., Zhao, H. et al. 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. Inflamm. Res. 70, 719–729 (2021). https://doi.org/10.1007/s00011-021-01472-z

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  • DOI: https://doi.org/10.1007/s00011-021-01472-z

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