CircMIRLET7BHG facilitates mast cell degranulation to accelerate allergic rhinitis progression by enhancing IL-33 mRNA stability via interacting with polypyrimidine tract–binding protein 1

BACKGROUND: Mast cell (MC) degranulation is associated with allergic rhinitis (AR) progression. Although circMIRLET7BHG has been identified as a promoter of AR development, its potential regulatory role in MC degranulation during AR progression has not been clarified. METHODS: MCs (LAD2) were co-cultured with ovalbumin (OVA)-induced human nasal mucosa epithelial cells (HNEpC), and an AR mouse model was generated through OVA stimulation. Nasal mucosal tissues were collected from 22 AR patients and 22 normal controls to detect the expression of circMIRLET7BHG and interleukin-33 (IL-33). The expression levels of circMIRLET7BHG and IL-33 were assessed by qRT-PCR, while cytokine production in MCs was quantified using ELISA. MCs degranulation was evaluated by toluidine blue staining, and western blotting was employed to detect the expression of polypyrimidine tract-binding protein 1 (PTBP1) and proteins related to mitochondrial fusion and fission. The interactions of PTBP1 with circMIRLET7BHG and IL-33 were verified by RNA immunoprecipitation and RNA pull-down assays, and IL-33 mRNA stability was determined using the actinomycin D assay. RESULTS: Co-culture of LAD2 cells with OVA-induced HNEpC demonstrated that circMIRLET7BHG knockdown inhibited MC degranulation by suppressing mitochondrial fission. circMIRLET7BHG and IL-33 levels were significantly increased in nasal tissues of AR patients compared with normal controls, showing a positive correlation between their expression levels. Mechanistically, circMIRLET7BHG enhanced IL-33 mRNA stability through its interaction with PTBP1. IL-33 overexpression promoted mitochondrial fission and accelerated MC degranulation, whereas this effect was reversed upon circMIRLET7BHG knockdown. In OVA-induced AR mouse models, circMIRLET7BHG overexpression increased epithelial thickness, eosinophil infiltration, and apoptosis, thereby aggravating allergic symptoms by enhancing mitochondrial fission and MC degranulation via upregulation of IL-33 expression. CONCLUSION: These findings demonstrate that circMIRLET7BHG promotes AR progression by enhancing mitochondrial fission and MC degranulation through regulation of the PTBP1/IL-33 axis, suggesting a potential novel therapeutic target for AR treatment.