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Background <p>Allergic asthma is driven by Th2-polarized immune responses, yet the epigenetic mechanisms underlying dendritic cell (DC)-mediated Th2 skewing remain unclear.</p> Methods <p>Using a house dust mite (DME)-induced murine asthma model, we combined pharmacological DNMT1 inhibition (5-Aza-2′-deoxycytidine, 5-azadC), DC-specific <i>Dnmt1</i> ablation (<i>Dnmt1</i><sup>fl/fl</sup> <i>Itgax-Cre</i> mice), chromatin immunoprecipitation (ChIP), RT-qPCR, and ubiquitination assays to dissect methylation-dependent regulation of IL-12b and TIM4 in DCs.</p> Results <p>Sensitization increased DNMT1 occupancy at the <i>Il12b</i> promoter, inducing hypermethylation (2.5-fold vs. naïve, <i>p</i> &lt; 0.001) and suppressing IL-12b expression (60% reduction, <i>p</i> &lt; 0.001). DNMT1 inhibition with 5-azadC or genetic <i>Dnmt1</i> ablation restored IL-12b levels (<i>p</i><i> &lt; 0.01</i>), reduced BALF Th2 cytokines (40–60%), eosinophils (62%), and mast cell mediators (<i>p</i><i> &lt; 0.01</i>), and attenuated airway inflammation. IL-12b promoted TIM4 degradation via Trim28-mediated K48-linked ubiquitination (<i>p</i><i> &lt; 0.01</i>), while <i>Il12b</i> deficiency sustained TIM4 expression and Th2 polarization. DNMT1 enrichment at the <i>Il12b</i> promoter correlated with TIM4 upregulation (<i>r</i> = 0.87, <i>p</i> &lt; 0.01), forming a self-reinforcing loop disrupted by <i>Timd4</i> knockdown.</p> Conclusion <p>DNMT1 in DCs orchestrates Th2 polarization via <i>Il12b</i> silencing and TIM4 stabilization, positioning DNMT1 inhibitors and TIM4-targeted therapies as novel strategies to rebalance Th1/Th2 responses in asthma.</p>

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Epigenetic reprogramming of dendritic cells by DNMT1 inhibition attenuates Th2 skewing in allergic airway inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月24日

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  • Jinmei Xue,
  • Yisha Wu,
  • Zhizhen Liu,
  • Siyu Duan,
  • Yongjin Ji,
  • Rui Dong,
  • Lei Lu,
  • Fangling Guan,
  • Zhigang Geng,
  • Yun Li,
  • Jiaqi Duan,
  • Jun Xie,
  • Pingchang Yang

摘要

Background

Allergic asthma is driven by Th2-polarized immune responses, yet the epigenetic mechanisms underlying dendritic cell (DC)-mediated Th2 skewing remain unclear.

Methods

Using a house dust mite (DME)-induced murine asthma model, we combined pharmacological DNMT1 inhibition (5-Aza-2′-deoxycytidine, 5-azadC), DC-specific Dnmt1 ablation (Dnmt1fl/fl Itgax-Cre mice), chromatin immunoprecipitation (ChIP), RT-qPCR, and ubiquitination assays to dissect methylation-dependent regulation of IL-12b and TIM4 in DCs.

Results

Sensitization increased DNMT1 occupancy at the Il12b promoter, inducing hypermethylation (2.5-fold vs. naïve, p < 0.001) and suppressing IL-12b expression (60% reduction, p < 0.001). DNMT1 inhibition with 5-azadC or genetic Dnmt1 ablation restored IL-12b levels (p < 0.01), reduced BALF Th2 cytokines (40–60%), eosinophils (62%), and mast cell mediators (p < 0.01), and attenuated airway inflammation. IL-12b promoted TIM4 degradation via Trim28-mediated K48-linked ubiquitination (p < 0.01), while Il12b deficiency sustained TIM4 expression and Th2 polarization. DNMT1 enrichment at the Il12b promoter correlated with TIM4 upregulation (r = 0.87, p < 0.01), forming a self-reinforcing loop disrupted by Timd4 knockdown.

Conclusion

DNMT1 in DCs orchestrates Th2 polarization via Il12b silencing and TIM4 stabilization, positioning DNMT1 inhibitors and TIM4-targeted therapies as novel strategies to rebalance Th1/Th2 responses in asthma.