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Published on: March 10, 2016
The SPRR2A-CSTA axis drives IL-17A-induced squamous metaplasia and steroid resistance in allergic rhinitis
Shaobing Xie1, Xuan Yuan1, Liyuan Liu2
1Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China.
Background:
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.
Objective:
We sought to define the epithelial keratinization program underlying SM in AR and determine its role in glucocorticoid resistance.
Methods:
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.
Results:
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.
Conclusions:
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.
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