Cell Communication and Signaling | DNMT1 regulates IL-12b and TIM4 expression in dendritic cells and affects allergic airway inflammation

This study reveals the molecular mechanism by which DNMT1 promotes Th2-type immune bias in dendritic cells through suppressing IL-12b and stabilizing TIM4 expression, providing novel epigenetic targets for allergic asthma treatment.

 

Literature Overview
The article "Epigenetic reprogramming of dendritic cells by DNMT1 inhibition attenuates Th2 skewing in allergic airway inflammation", published in Cell Communication and Signaling, reviews DNMT1's role in regulating IL-12b and TIM4 expression in dendritic cells (DCs) and its feedback regulatory mechanisms on Th2 polarization. The study further elucidates DNMT1's molecular pathways in DNA methylation and histone modification at the Il12b promoter region, validated through DC-specific gene knockout and pharmacological interventions to assess their impact on allergic airway inflammation.

Background Knowledge
Allergic asthma is a Th2 cell-mediated chronic airway inflammatory disease characterized by elevated cytokines such as IL-4, IL-5, and IL-13, along with airway hyperresponsiveness. DNA methylation, as a key epigenetic modification mechanism, participates in gene expression regulation and immune cell differentiation. DNMT1, the major maintenance DNA methyltransferase, has not been fully characterized in DC function. TIM4, a DC-specific receptor enhancing Th2 differentiation, remains unclear in its expression regulatory mechanisms. Based on a house dust mite (HDM)-induced mouse asthma model combined with DNMT1-specific knockout mice and pharmacological inhibitor 5-azadC, this study systematically analyzes DNMT1's role in DCs and its regulatory mechanisms on Th2 polarization, providing novel epigenetic intervention targets for asthma treatment.

 

 

Research Methods and Experiments
The study employed an HDM-induced mouse allergic airway inflammation model combined with pharmacological inhibition of DNMT1 (5-azadC) and DC-specific Dnmt1 knockout (Dnmt1fl/fl Itgax-Cre) mice to analyze DNMT1's regulatory role in Il12b and Tim4 expression. Researchers evaluated DNA methylation status in the Il12b promoter region, DNMT1 binding levels, and TIM4 ubiquitination status through ChIP, RT-qPCR, and ubiquitination assays. Additionally, the effects of 5-azadC on airway inflammation, Th2 cytokine levels in BALF, and Th2 polarization following DC-CD4+ T cell co-culture were assessed.

Key Conclusions and Perspectives

• In the allergic asthma model, DCs exhibit significant downregulation of Il12b expression while DNMT1 binding at the Il12b promoter region increases, leading to DNA hypermethylation in this area.
• 5-azadC treatment or DC-specific Dnmt1 deletion restores Il12b expression, reduces Th2 cytokines, eosinophil levels, and mast cell mediator release, alleviating airway inflammation.
• IL-12b enhances TIM4 degradation through Trim28-mediated K48 ubiquitination, while Il12b deficiency causes stable TIM4 expression, amplifying Th2 polarization.
• DNMT1 and TIM4 form a positive feedback regulatory loop: DNMT1 enrichment at the Il12b promoter correlates strongly with TIM4 expression (r = 0.87, p < 0.01), and Timd4 knockout blocks DNMT1 recruitment.
• This study demonstrates DNMT1's dual mechanism (Il12b silencing and TIM4 stabilization) in promoting Th2 polarization in DCs, suggesting DNMT1 inhibitors and TIM4-targeted therapies could represent novel immunomodulatory strategies for asthma.

Research Significance and Prospects
This work first reveals DNMT1's epigenetic regulatory mechanism in DC-mediated Th2 polarization, proposing the DNMT1-TIM4 feedback loop as a potential therapeutic target. Future studies should verify this pathway's conservation in human DCs and evaluate DNMT1 inhibitors' long-term safety in chronic allergy models. Combining TIM4 blocking antibodies or RNAi strategies may enhance 5-azadC efficacy, providing precision intervention protocols for Th2-dominant asthma phenotypes.

 

 

Conclusion
In summary, this study utilized an HDM-induced mouse asthma model combined with pharmacological DNMT1 inhibition and DC-specific gene knockout experiments to elucidate DNMT1's critical role in allergic airway inflammation. Researchers found DNMT1 suppresses Il12b expression through DNA methylation at its promoter region while promoting TIM4 stabilization, thereby amplifying Th2-type immune responses. 5-azadC treatment reverses these effects, restoring Il12b expression and reducing TIM4 levels to inhibit allergic inflammation. Notably, LPS partially rescues DME-induced Il12b downregulation, suggesting TLR4 signaling as a potential adjuvant therapeutic target. These findings provide new insights into epigenetic asthma treatments and establish mechanistic foundations for targeting DNMT1 and TIM4 in immunomodulation. Future studies should validate this mechanism in human DCs and explore synergistic therapeutic effects of combined DNMT1 inhibitors and TIM4 blockers to develop more effective intervention strategies for Th2-high inflammatory asthma patients.

 

Jinmei Xue, Yisha Wu, Zhizhen Liu, Jun Xie, and Pingchang Yang. Epigenetic reprogramming of dendritic cells by DNMT1 inhibition attenuates Th2 skewing in allergic airway inflammation. Cell Communication and Signaling : CCS.