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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.
The Journal of Allergy and Clinical Immunology
|June 10, 2026
Summary
The SPRR2A-CSTA pathway drives squamous metaplasia and steroid resistance in allergic rhinitis (AR). Targeting this axis offers a new therapeutic strategy for refractory AR.
Area of Science:
- Immunology and Dermatology
- Epithelial Biology
- Molecular Medicine
Background:
- Refractory allergic rhinitis (AR) involves understudied epithelial alterations like squamous metaplasia (SM).
- The molecular mechanisms driving SM and its link to steroid resistance in AR are not well understood.
Purpose of the Study:
- To elucidate the epithelial keratinization program in SM within AR.
- To determine the role of this program in glucocorticoid resistance.
Main Methods:
- Immunostaining and transcriptomic profiling of nasal mucosa from AR patients.
- Utilizing Sprr2a-deficient mice and primary nasal epithelial cells to study keratinization and steroid response.
- Quantifying serum SPRR2A and CSTA levels in AR patients stratified by steroid responsiveness.
Main Results:
- SPRR2A was identified as a key marker for SM in AR, associated with keratin remodeling (KRT6A, KRT13).
- Increased GRβ, a steroid resistance mediator, co-localized with KRT6A/KRT13 in SM tissues.
- IL-17A induced SPRR2A-driven keratinization, creating a steroid-resistant state; Sprr2a deficiency blocked this and restored steroid sensitivity.
- CSTA was identified as a SPRR2A-dependent effector promoting squamous differentiation and GRβ induction, recapitulating SM and steroid resistance in vitro.
- Elevated serum SPRR2A and CSTA levels correlated with steroid resistance in AR patients.
Conclusions:
- The SPRR2A-CSTA axis promotes epithelial squamous metaplasia and steroid resistance in allergic rhinitis.
- This pathway represents a potential therapeutic target and biomarker for refractory AR.
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