The SPRR2A-CSTA axis drives IL-17A-induced squamous metaplasia and steroid resistance in allergic rhinitis.

Abstract

Epithelial remodeling, particularly squamous metaplasia (SM), is a common but understudied epithelial alteration in refractory allergic rhinitis (AR). Its molecular drivers and contribution to steroid resistance remain unclear. We sought to define the epithelial keratinization program underlying SM in AR and determine its role in glucocorticoid resistance. Nasal mucosa tissues from patients with refractory AR with or without SM were assessed by immunostaining and transcriptomic profiling. Small proline-rich protein 2A (SPRR2A)-deficient mice were used to determine the role of SPRR2A in epithelial keratinization and steroid responsiveness. Primary nasal epithelial cells were stimulated with IL-17A or cystatin A (CSTA) to evaluate SPRR2A-dependent keratinization and steroid resistance. Serum SPRR2A and CSTA levels were quantified in patients with AR stratified by steroid responsiveness. Transcriptomic analysis identified SPRR2A as a leading epithelial marker associated with SM in AR. SPRR2A-associated keratin remodeling, including upregulation of KRT6A and KRT13, represented a defining molecular signature of SM. Glucocorticoid receptor β, a key mediator of steroid resistance, was markedly increased and colocalized with KRT6A and KRT13 in SM tissues. IL-17A induced a robust SPRR2A-keratin remodeling module, generating a steroid-resistant epithelial state. Genetic deletion of Sprr2a abolished IL-17A-driven keratinization, prevented SM, and restored steroid responsiveness. Mechanistically, CSTA emerged as a SPRR2A-dependent effector that promoted squamous differentiation and epithelial GRβ induction. Csta-treated primary cultures recapitulated SM and conferred steroid resistance. Clinically, elevated serum SPRR2A and CSTA levels distinguished patients with steroid-resistant AR from those with steroid-responsive AR. SPRR2A promotes epithelial SM and steroid resistance through CSTA, identifying the SPRR2A-CSTA axis as a potential therapeutic target and biomarker pathway in refractory AR.