Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation

doi:10.1016/j.jaci.2025.05.012

. 2025 May 28:S0091-6749(25)00578-0.

doi: 10.1016/j.jaci.2025.05.012. Online ahead of print.

Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation

Shaobing Xie¹, Sijie Jiang², Xuan Yuan¹, Liyuan Liu³, Maonan Wu⁴, Wenjing Gu⁵, Hua Zhang⁶, Zhihai Xie⁶, Weihong Jiang⁷, Peisong Gao⁸

Affiliations

¹ Division 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.
² Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China.
³ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md.
⁴ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Pediatric Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁵ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
⁶ Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁷ Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address: jiangwh68@126.com.
⁸ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address: pgao1@jhmi.edu.

PMID: 40447198
PMCID: PMC12277033 (available on 2026-05-28)
DOI: 10.1016/j.jaci.2025.05.012

Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation

Shaobing Xie et al. J Allergy Clin Immunol. 2025.

. 2025 May 28:S0091-6749(25)00578-0.

doi: 10.1016/j.jaci.2025.05.012. Online ahead of print.

Authors

Shaobing Xie¹, Sijie Jiang², Xuan Yuan¹, Liyuan Liu³, Maonan Wu⁴, Wenjing Gu⁵, Hua Zhang⁶, Zhihai Xie⁶, Weihong Jiang⁷, Peisong Gao⁸

Affiliations

¹ Division 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.
² Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China.
³ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md.
⁴ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Pediatric Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁵ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
⁶ Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁷ Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address: jiangwh68@126.com.
⁸ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address: pgao1@jhmi.edu.

PMID: 40447198
PMCID: PMC12277033 (available on 2026-05-28)
DOI: 10.1016/j.jaci.2025.05.012

Abstract

Background: Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is a severe subtype of chronic rhinosinusitis characterized by eosinophilic inflammation, type 2 immune responses, and tissue remodeling in the sinonasal mucosa.

Objective: We sought to identify genes contributing to eCRSwNP pathogenesis and elucidate their roles in epithelial dysfunction and tissue remodeling.

Methods: Transcriptome sequencing was conducted on nasal tissues from patients with eCRSwNP, noneosinophilic CRSwNP (neCRSwNP), and healthy controls and from a CRSwNP mouse model with small proline-rich protein 2A knockout (Sprr2a^-/-) mice. Epithelial-mesenchymal transition (EMT) was examined in the CRSwNP mouse model and air-liquid interface culture system with nasal epithelial cells.

Results: Transcriptomic analysis revealed that SPRR2A expression was significantly elevated in eCRSwNP nasal tissues compared with neCRSwNP and healthy controls. High SPRR2A expression correlated with increased eosinophil infiltration, epithelial thickness, and IL-13 levels. In the CRSwNP mouse model, Sprr2a^-/- mice displayed reduced epithelial thickness, fewer nasal polyps, lower IL-4 and IL-13 levels, and attenuated EMT. In vitro, nasal epithelial cells from Sprr2a^-/- mice demonstrated reduced EMT markers and preserved barrier integrity. Further transcriptomic analysis identified serum amyloid A3 (Saa3) as a downstream mediator of SPRR2A. Saa3 expression was reduced in Sprr2a^-/- mice, whereas serum amyloid A2 (SAA2 [human]) was upregulated in eCRSwNP compared with neCRSwNP and healthy controls and positively correlated with SPRR2A levels. In air-liquid interface cultures, Saa3 induced EMT and barrier dysfunction and increased IL-6, thymic stromal lymphopoietin, IL-33, and TGF-β1 production.

Conclusions: These findings suggest that SPRR2A promotes eosinophilic inflammation and tissue remodeling via SAA2, highlighting the SPRR2A-SAA2 axis as a potential therapeutic target in eCRSwNP.

Keywords: Chronic rhinosinusitis with nasal polyps; air-liquid interface; epithelial-mesenchymal transition; serum amyloid A3; small proline-rich protein 2A; tissue remodeling.

PubMed Disclaimer

Conflict of interest statement

Disclosure statement This study was supported by grants from the National Institutes of Health (grant nos. 1R01AI153331 and R01AI141642) and the National Natural Science Foundation of China (grant nos. 82371126, 82371127, and 82301289). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

References

1. Fokkens WJ, Viskens AS, Backer V, Conti D, De Corso E, Gevaert P, et al. EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023. Rhinology 2023;61:194–202. - PubMed
1. Hopkins C Chronic rhinosinusitis with nasal polyps. N Engl J Med 2019;381: 55–63. - PubMed
1. McCormick JP, Thompson HM, Cho DY, Woodworth BA, Grayson JW. Phenotypes in chronic rhinosinusitis. Curr Allergy Asthma Rep 2020;20:20. - PubMed
1. Wang H, Do DC, Liu J, Wang B, Qu J, Ke X, et al. Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 2018;141:586–600.e6. - PMC - PubMed
1. Yang T, Wan R, Tu W, Avvaru SN, Gao P. Aryl hydrocarbon receptor: linking environment to aging process in elderly patients with asthma. Chin Med J (Engl) 2024;137:382–93. - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science
Miscellaneous
- NCI CPTAC Assay Portal

[1] Fokkens WJ, Viskens AS, Backer V, Conti D, De Corso E, Gevaert P, et al. EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023. Rhinology 2023;61:194–202. - PubMed

[2] Fokkens WJ, Viskens AS, Backer V, Conti D, De Corso E, Gevaert P, et al. EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023. Rhinology 2023;61:194–202. - PubMed

[3] Hopkins C Chronic rhinosinusitis with nasal polyps. N Engl J Med 2019;381: 55–63. - PubMed

[4] Hopkins C Chronic rhinosinusitis with nasal polyps. N Engl J Med 2019;381: 55–63. - PubMed

[5] McCormick JP, Thompson HM, Cho DY, Woodworth BA, Grayson JW. Phenotypes in chronic rhinosinusitis. Curr Allergy Asthma Rep 2020;20:20. - PubMed

[6] McCormick JP, Thompson HM, Cho DY, Woodworth BA, Grayson JW. Phenotypes in chronic rhinosinusitis. Curr Allergy Asthma Rep 2020;20:20. - PubMed

[7] Wang H, Do DC, Liu J, Wang B, Qu J, Ke X, et al. Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 2018;141:586–600.e6. - PMC - PubMed

[8] Wang H, Do DC, Liu J, Wang B, Qu J, Ke X, et al. Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 2018;141:586–600.e6. - PMC - PubMed

[9] Yang T, Wan R, Tu W, Avvaru SN, Gao P. Aryl hydrocarbon receptor: linking environment to aging process in elderly patients with asthma. Chin Med J (Engl) 2024;137:382–93. - PMC - PubMed

[10] Yang T, Wan R, Tu W, Avvaru SN, Gao P. Aryl hydrocarbon receptor: linking environment to aging process in elderly patients with asthma. Chin Med J (Engl) 2024;137:382–93. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation

Affiliations

Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation

Authors

Affiliations

Abstract

Conflict of interest statement

Similar articles

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous

Abstract

Conflict of interest statement

Similar articles

References

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous