Allergic rhinitis (AR) is a chronic inflammatory upper airway disease characterized by itchy nose, stuffy nose, paroxysmal repetitive sneezing and watery rhinorrhea (Wheatley and Togias, 2015). In the early response of AR, inhaled allergens invade the nasal mucosal epithelial cells to bind to immunoglobulin E (IgE) antibodies on mast cells distributed over the nasal mucosa, thereby resulting in the release of chemical mediators, such as histamine. These may directly activate T-helper 2 (Th2) cells to release Th2 cytokines (such as interleukin(IL)−4, IL-13), which further stimulate B cells to synthesize IgE, disrupt mucosal barrier and trigger eosinophil infiltration, thus enhancing allergic inflammation (Barnes, 2011). AR occurs in over 500 million people worldwide, with 25 million of the affected people living in China (Zhang and Zhang, 2020). With a considerable increase in air pollutant levels and climate change, the incidence and prevalence of AR continue to rise in China (Zhang and Zhang, 2019). AR negatively impacts productivity and quality of life in children and adults due to the long course and repeated attacks. Antihistamines, corticosteroids and decongestants are currently effective drugs for the treatment of AR, however, their transient efficacy and adverse effects make AR not easy to cure (Meltzer et al., 2012). Therefore, a novel safe and effective therapy for AR is urgently needed.

Forkhead box C1 (FOXC1), a member of the Fox family of transcription factors, promotes the pathology of chronic inflammatory diseases, such as osteoarthritis and rheumatoid arthritis (Wang et al., 2020a, Wang et al., 2020b). A previous study showed that treatment with isorhynchophylline attenuated allergic asthma symptoms by reducing FOXC1 expression, indicating that FOXC1 may contribute to the progression of asthma (Zhu et al., 2020). Analysis of gene expression profiles (Gene Expression Omnibus (GEO) database, accession GSE9150) revealed that FOXC1 was up-regulated in nasal epithelial cells derived from AR patients (Vroling et al., 2008). This implied that FOXC1 may participate in AR pathogenesis. Researchers found that high expression of DNA methyltransferases (DNMTs), including DNMT1, DNMT3A and DNMT3B, increased the interferon-γ promoter methylation in CD4+ T cells and induced a shift of the Th1/Th2 balance toward Th2, thereby exacerbating AR (Ai et al., 2020, Li et al., 2019). Knocking down DNMTs also reversed the suppression of TGF-β1-induced epithelial marker E-cadherin expression in nasal epithelial cells (Park et al., 2022). Lin et al. (2021) demonstrated that FOXC1 promoted cancer malignant phenotypes by upregulating DNMT3B to induce DNA methylation of cystathionine γ-lyase promoter (Lin et al., 2021). Nevertheless, whether FOXC1 affects AR progression through regulating DNM3B remains unknown.

In our previous study, overexpression of secreted frizzled-related protein 5 (SFRP5) relieved IL-13-induced inflammation in human nasal epithelial cells (HNEpCs) (Shi et al., 2021). In addition, upregulation of DNMTs was revealed to reduce SFRP5 expression by promoter methylation in tumor cells (Linhart et al., 2007, Xie et al., 2014). Based on these findings, we speculate that FOXC1 may influence the development of AR by regulating DNMTs-mediated SFRP5 promoter methylation. For this purpose, ovalbumin (OVA)-induced AR murine model was established to assess the effect of FOXC1 on the pathophysiological properties in AR. Further, air-liquid interface (ALI) cultures of HNEpCs were used to evaluate the effect of FOXC1 on IL-13-driven epithelial barrier disruption.