| First Author | Xue J | Year | 2025 |
| Journal | Cell Commun Signal | Volume | 23 |
| Issue | 1 | Pages | 459 |
| PubMed ID | 41136987 | Mgi Jnum | J:374410 |
| Mgi Id | MGI:8256780 | Doi | 10.1186/s12964-025-02467-7 |
| Citation | Xue J, et al. (2025) Epigenetic reprogramming of dendritic cells by DNMT1 inhibition attenuates Th2 skewing in allergic airway inflammation. Cell Commun Signal 23(1):459 |
| abstractText | 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 (Dnmt1(fl/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. naive, 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02467-7. |
