Inhibition of DNA Methyltransferase DNMT1 Reverses Th2 Response Polarisation and Alleviates Allergic Rhinitis

Abstract

Background

Type 2 T helper (Th2) cells-mediated immune response plays vital roles in allergic rhinitis (AR), and DNA methylation is previously found to be closely related to AR development.

Aims

Our study aims to reveal the detail mechanism of DNA methylation affecting Th2 response in AR.

Methods

Mice were stimulated with ovalbumin (OVA) to induce AR symptoms, and CD4⁺ T cells were subjected to Th2 induction culture. Real-time quantitative PCR, western blot, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyse the activation of Th2 response.

Results

DNA methyltransferase 1 (DNMT1) was significantly upregulated in OVA-induced AR model mice, and DNMT1 knockdown alleviated AR symptoms and pathological changes of nasal mucosa tissues in the model mice. DNMT1 knockdown obviously reduced the expression of GATA binding protein 3 (GATA3), the ratio of interleukin (IL)-4⁺CD4⁺ cells and the release of Th2 cytokines, but elevated the expression of T-box expressed in T cells (T-bet), the ratio of interferon (IFN)-γ⁺CD4⁺ cells and the levels of Th1 cytokines to improve Th1/Th2 imbalance in the model mice and Th2-induced CD4⁺T cells. Mechanistically, DNMT1 promoted promoter methylation of forkhead box O3 (FOXO3), inhibited FOXO3 expression and activated the nuclear factor kappa-B (NF-κB)/GATA3 signalling. FOXO3 overexpression remarkably inactivated the NF-κB/GATA3 pathway and mitigated Th2 polarisation in DNMT1-deficient and Th2-conditined CD4⁺T cells, which was reversed by a NF-κB inhibitor.

Conclusion

Altogether, DNMT1 downregulated FOXO3 expression to activate the NF-κB/GATA3 pathway and promote Th2 response in AR.