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YTHDF1-mediated mitochondrial dysfunction and allergic airway inflammation by interaction with β-catenin/TCF4
Cancan Xie1, Junwen Huang2, Ying Chen2
1Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangdong 510515, China; Department of Critical Care Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 412007, China.
Background:
Although N6-methyladenosine (m6A) modification and its reader protein YTHDF1 have been implicated in allergic airway inflammation, their roles in TDI-induced steroid-insensitive asthma remains unclear. β-catenin signaling is vital for airway inflammation and mitochondrial function in asthma. In this study, we investigated the interplay between β-catenin/TCF4 signaling and m6A-dependent regulation in a TDI-induced asthma model (TDI-AM).
Method:
Mice were sensitized and challenged with TDI or house dust mite (HDM) to establish asthma models. Mice were administered the YHTDF1 m6A modification inhibitor (Tegaserod), the β-catenin/TCF4 signaling inhibitor (LF3), and the mitochondrial stabilizing drug SS-31 triacetate. Human serum albumin-containing TDI was introduced to human bronchial epithelial cells and macrophages to mimic the asthma model.
Result:
YTHDF1 was upregulated in the TDI-AM. Pretreatment with a 1 mg/kg concentration of Tegaserod in TDI-AM revealed significant alleviation of TDI-induced airway hyperresponsiveness, airway inflammation, airway remodeling, and mitochondrial dysfunction, but pretreatment with 5 mg/kg concentration of Tegaserod showed the opposite effect. The changes above corroborated in HDM-induced asthmatic mice. JASPAR software predicted the β-catenin signaling downstream transcription factor TCF4 combined with YTHDF1 promoter region, suggesting a possible interaction between TCF4 and YTHDF1. Blockade of β-catenin/TCF4 signaling with LF3 largely inhibited airway inflammation, mitochondrial dysfunction, and the expression of YTHDF1 in the TDI-AM. Treatment with LF3 can significantly inhibit the expression of YTHDF1 protein. The TDI-induced airway inflammation, as well as mitochondrial dysfunction, were both significantly decreased after treatment with SS-31 triacetate.
Conclusion:
YTHDF1-mediated mitochondrial dysfunction and allergic airway inflammation by interaction with β-catenin/TCF4 signaling.
Insights
N6-methyladenosine (m6A) reader YTHDF1 exacerbates steroid-insensitive asthma by impairing mitochondrial function via β-catenin/TCF4 signaling. Inhibiting YTHDF1 or β-catenin/TCF4 signaling alleviates airway inflammation and mitochondrial dysfunction in asthma models.
Area of Science:
- Immunology
- Molecular Biology
- Respiratory Medicine
Background:
- N6-methyladenosine (m6A) modification and YTHDF1 are linked to allergic airway inflammation.
- The role of m6A and YTHDF1 in toluene diisocyanate (TDI)-induced steroid-insensitive asthma is not well understood.
- β-catenin signaling is crucial for airway inflammation and mitochondrial function in asthma.
Purpose of the Study:
- To investigate the interplay between β-catenin/TCF4 signaling and m6A-dependent regulation in a TDI-induced asthma model.
- To explore the role of YTHDF1 in TDI-induced steroid-insensitive asthma.
Main Methods:
- Established mouse models of asthma using TDI or house dust mite (HDM) sensitization and challenge.
- Administered YTHDF1 inhibitor (Tegaserod), β-catenin/TCF4 inhibitor (LF3), and mitochondrial stabilizer (SS-31 triacetate).
- Utilized human bronchial epithelial cells and macrophages exposed to TDI for in vitro studies.
Main Results:
- YTHDF1 was upregulated in the TDI-induced asthma model (TDI-AM).
- Low-dose Tegaserod alleviated airway hyperresponsiveness, inflammation, remodeling, and mitochondrial dysfunction in TDI-AM and HDM models.
- LF3 inhibited airway inflammation, mitochondrial dysfunction, and YTHDF1 expression, suggesting YTHDF1 interacts with β-catenin/TCF4 signaling.
- SS-31 triacetate treatment reduced TDI-induced airway inflammation and mitochondrial dysfunction.
Conclusions:
- YTHDF1 mediates mitochondrial dysfunction and allergic airway inflammation through interaction with β-catenin/TCF4 signaling.
- Targeting YTHDF1 or β-catenin/TCF4 signaling may offer therapeutic strategies for steroid-insensitive asthma.
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