Epithelial cell dynamics: Key drivers of type 2 inflammation in eosinophilic chronic rhinosinusitis

Sinonasal mucosal epithelial cells act not only as a physical barrier, but also as dynamic regulators of immune responses through innate and acquired immunity. These cells play a key role in detecting environmental stimuli, such as pathogens, allergens, and pollutants, and in initiating the inflammatory cascade that shapes the overall immune response. By releasing cytokines, such as interleukin (IL)-25 and IL-33, and thymic stromal lymphopoietin, epithelial cells interact with immune cells and promote type 2 inflammation. The pathogenesis of eosinophilic chronic rhinosinusitis (ECRS), which is driven by type 2 inflammation, is heterogeneous. While immune cells have traditionally been considered to be central to the disease pathogenesis, emerging evidence has indicated the critical role of epithelial cells. Furthermore, novel biologics targeting the IL-4/IL-13 signaling pathway have shown potential in alleviating epithelial dysfunction and inflammation. Eosinophilic mucins that accumulate in the sinuses impair mucociliary function, and especially eosinophil extracellular trap cell death (EETosis) stimulate epithelial cells and amplify eosinophilic inflammation. Eosinophilic mucin formation has been shown to significantly increase viscosity through EETosis, and novel biologics targeting the IL-5 signaling pathway hold promise for effectively mitigating this process. To develop targeted interventions, it is important to explore the role of epithelial subpopulations, such as basal cells and tuft cells, in maintaining the balance between tissue repair and chronic inflammation. Single-cell transcriptomics and spatial transcriptomics technologies have provided significant insights into the complexity of epithelial cell-derived inflammation in ECRS. The heterogeneity of the pathogenesis of CRS with nasal polyps and ECRS across patient populations complicates the development of universal therapies, underscoring the need for stratified medicine approaches. Potential future therapeutic strategies include the restoration of epithelial integrity and immune balance by disrupting aberrant crosstalk between epithelial and immune cells, particularly in patients unresponsive to current treatments.