YTHDF1-mediated mitochondrial dysfunction and allergic airway inflammation by interaction with β-catenin/TCF4 signaling

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.