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Role of LINC00240 on T-helper 9 differentiation in allergic rhinitis through influencing DNMT1-dependent methylation of PU.1

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Abstract

Background

Allergic rhinitis (AR) is a common allergic disease with increasing prevalence globally. However, the molecular mechanism underlying AR pathogenesis remains largely undefined.

Methods

Peripheral blood and nasal mucosa samples obtained from patients with AR (n = 22), and ovalbumin-induced AR mouse model (n = 8 per group) were prepared for subsequent detection. qRT-PCR and western blot were used to detect the expression of LINC00240, miR-155-5p, PU.1 and other key molecules. ELISA assay and flow cytometry were employed to evaluate the secretion of IL-9 and T-helper 9 (Th9) cell ratio, respectively. Bioinformatics analysis, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and luciferase reporter assays were employed to further elucidate the regulatory network of LINC00240/miR-155-5p/DNMT1. The methylation of PU.1 promoter was assessed by methylation-specific PCR (MSP). This signaling axis was further validated in the mouse model of AR.

Results

LINC00240 was downregulated, while miR-155-5p and PU.1 were upregulated in the peripheral blood and nasal mucosa of AR patients, as well as in AR mice. This was accompanied with the increased ratio of Th9 cells and elevated IL-9 secretion. Mechanistically, LINC00240 served as a miR-155-5p sponge, and DNMT1 was a target of miR-155-5p. In addition, DNMT1 mediated the methylation of PU.1 promoter. In vivo studies verified that LINC00240 mitigated AR progression, possibly via miR-155-5p/DNMT1/PU.1-dependent Th9 differentiation.

Conclusion

The involvement of LINC00240 in AR pathogenesis is closely associated with Th9 differentiation through modulating DNMT1-dependent methylation of PU.1 by sponging miR-155-5p.

Highlights

LINC00240 was downregulated, while miR-155-5p and PU.1 were upregulated in the serum and nasal mucosa of AR patients and mice.

The percentage of Th9 cells and IL-9 secretion were elevated in AR patients and mice.

LINC00240 served as a miR-155-5p sponge, and DNMT1 was a target of miR-155-5p.

DNMT1 mediated the methylation of PU.1 promoter.

LINC00240/miR-155-5p/DNMT1/PU.1 axis is involved in AR pathogenesis via modulating Th9 differentiation.

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Data Availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Abbreviations

5-Aza:

5-Azacytidine

AD:

Atopic dermatitis

AR:

Allergic rhinitis

ChIP:

Chromatin immunoprecipitation

DNMT:

DNA methyltransferase

ELISA:

Enzyme-linked immunosorbent assay

FISH:

Fluorescence in situ hybridization

GC:

Gastric cancer

HCC:

Hepatocellular carcinoma

H&E:

Hematoxylin & Eosin

IgE:

Immunoglobulin E

IL-4:

Interleukin-4

ILC2s:

Group 2 innate lymphoid cells

lncRNA:

Long non-coding RNA

MSP:

Methylation-specific PCR

MUT:

Mutated

OVA:

Ovalbumin

NPC:

Nasopharyngeal carcinoma

NSCLC:

Non-small cell lung cancer

RIP:

RNA immunoprecipitation

SPF:

Specific-pathogen-free

TGF-β:

Transforming growth factor-β

Th9:

T-helper 9

WT:

Wild type

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Funding

This study was funded by the Applied Research training program of Science and Technology Department of Jiangxi province (No.20212BAG70031), the National Natural Science Foundation of China (No. 82160211) and the Jiangxi Provincial Natural Science Foundation (No. 20202ACBL206013).

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Authors and Affiliations

  1. Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi Province, P.R. China

    JianGuo Liu, XunShuo Jiang, Ke Liu, JianJian Deng, Yi Qiu, Wan Wei & ChunPing Yang

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Contributions

Conception and design of study: C. Y. Acquisition of data: J. L.; K. L.; Y. Q. Analysis and interpretation of data: X. J.; J. D.; W. W. Drafting the manuscript: J. L. Revising the manuscript critically for important intellectual content: C. Y. All authors reviewed the manuscript.

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Correspondence to ChunPing Yang.

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This study has obtained approval of the Ethics Committee of The Second Affiliated Hospital of Nanchang University and the patient’s written informed consent.

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Liu, J., Jiang, X., Liu, K. et al. Role of LINC00240 on T-helper 9 differentiation in allergic rhinitis through influencing DNMT1-dependent methylation of PU.1. Immunol Res 72, 197–211 (2024). https://doi.org/10.1007/s12026-023-09435-8

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