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Published on: July 10, 2018
DNMT3A-mediated Methylation of IRF4 Alleviates Inflammatory Response in Allergic Rhinitis Mice
Dan Shan1, Simin Gao2, Lin Li1
1Department of Otorhinolaryngology Head and Neck Surgery, Sleep Medicine Center, West China School of Public Health, Sichuan University West China Fourth Hospital, No. 18, Section 3, Renmin South Road, Wuhou District, Chengdu City, Sichuan Province, China.
Abstract:
This study explores the mechanism of DNMT3A in inflammatory response in allergic rhinitis (AR) mice. A mouse model of AR was established by ovalbumin induction, followed by injection of DNMT3A overexpression vector. The times of nose rubbing and sneezing within 15 min were recorded. The nasal mucosa tissues were observed by H&E staining. The serum histamine, IgE, IL-1β, IL-10, IFN-γ, and TNF-α were detected by ELISA. The proportion of Th17/Treg cells in lymphocytes was detected by flow cytometry. DNMT3A, IRF4, and CD44 expressions were tested by qRT-PCR or Western blot. ChIP evaluated the DNMT3A enrichment on IRF4 promoter and IRF4 enrichment on CD44 promoter. Methylation-specific PCR determined the methylation level of IRF4 promoter. The binding of IRF4 to CD44 was verified by dual-luciferase assay. DNMT3A was poorly expressed in AR mice. DNMT3A overexpression reduced the times of nose rubbing and sneezing in AR mice, alleviated nasal mucosal tissue injury, reduced the proportion of Th17/Treg cells, and diminished serum inflammatory factors. DNMT3A was enriched on IRF4 promoter and repressed IRF4 expression by enhancing IRF4 methylation level. IRF4 bound to CD44 promoter to elevate CD44 expression. In conclusion, DNMT3A-mediated methylation of IRF4 reduces AR inflammatory response by elevating CD44 expression.
Insights
DNA methyltransferase 3A (DNMT3A) suppresses allergic rhinitis (AR) inflammation by methylating IRF4, which reduces Th17/Treg imbalance and inflammatory factors, ultimately alleviating AR symptoms.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Allergic rhinitis (AR) involves complex inflammatory responses.
- The role of DNA methyltransferase 3A (DNMT3A) in AR pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the mechanism of DNMT3A in regulating inflammatory responses in a mouse model of allergic rhinitis.
- To elucidate the molecular pathway involving DNMT3A, IRF4, and CD44 in AR.
Main Methods:
- Established an ovalbumin-induced AR mouse model.
- Utilized DNMT3A overexpression vectors, ELISA, qRT-PCR, Western blot, ChIP, and dual-luciferase assays.
- Analyzed behavioral symptoms, nasal tissue histology, serum inflammatory markers, and immune cell populations.
Main Results:
- DNMT3A overexpression significantly reduced AR symptoms, nasal tissue damage, Th17/Treg cell imbalance, and serum inflammatory factors.
- DNMT3A was found to be poorly expressed in AR mice and repressed IRF4 expression via methylation.
- IRF4 was shown to bind the CD44 promoter, upregulating CD44 expression.
Conclusions:
- DNMT3A plays a protective role in allergic rhinitis by suppressing inflammation.
- The DNMT3A-IRF4-CD44 axis is a key regulatory pathway in AR.
- DNMT3A-mediated methylation of IRF4 reduces AR inflammatory response by elevating CD44 expression.
