Current Understanding of Epithelial-Derived Alarmins in Chronic Rhinosinusitis with Nasal Polyps

doi:10.1007/s12016-025-09073-y

Review

. 2025 Jun 18;68(1):59.

doi: 10.1007/s12016-025-09073-y.

Current Understanding of Epithelial-Derived Alarmins in Chronic Rhinosinusitis with Nasal Polyps

Fuying Cheng^#^{1

2

3}, Yizhang Wang^#^{1

2}, Yingqi Gao^{1

2}, Chen Zhang^{1

2}, Qianqian Zhang^{1

2}, Jiani Chen^{1

2}, Yumin Zhou^{1

2}, Le Shi^{1

2}, Li Hu^{1

2}, Huan Wang^{4

5}, Yaguang Zhang^{6

7}, Xicai Sun^{8

9}

Affiliations

¹ High Altitude Rhinology Research Center, Eye & ENT Hospital of Fudan University and People's Hospital of Shigatse City, Shanghai, Shigatse, China.
² ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China.
³ Med-X Institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi, China.
⁴ High Altitude Rhinology Research Center, Eye & ENT Hospital of Fudan University and People's Hospital of Shigatse City, Shanghai, Shigatse, China. huanwang14@fudan.edu.cn.
⁵ ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China. huanwang14@fudan.edu.cn.
⁶ Med-X Institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi, China. zhangyaguang@xjtufh.edu.cn.
⁷ Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China. zhangyaguang@xjtufh.edu.cn.
⁸ High Altitude Rhinology Research Center, Eye & ENT Hospital of Fudan University and People's Hospital of Shigatse City, Shanghai, Shigatse, China. laryngeal@163.com.
⁹ ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China. laryngeal@163.com.

^# Contributed equally.

PMID: 40533675
DOI: 10.1007/s12016-025-09073-y

Review

Current Understanding of Epithelial-Derived Alarmins in Chronic Rhinosinusitis with Nasal Polyps

Fuying Cheng et al. Clin Rev Allergy Immunol. 2025.

. 2025 Jun 18;68(1):59.

doi: 10.1007/s12016-025-09073-y.

Authors

Affiliations

¹ High Altitude Rhinology Research Center, Eye & ENT Hospital of Fudan University and People's Hospital of Shigatse City, Shanghai, Shigatse, China.
² ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China.
³ Med-X Institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi, China.
⁴ High Altitude Rhinology Research Center, Eye & ENT Hospital of Fudan University and People's Hospital of Shigatse City, Shanghai, Shigatse, China. huanwang14@fudan.edu.cn.
⁵ ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China. huanwang14@fudan.edu.cn.
⁶ Med-X Institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi, China. zhangyaguang@xjtufh.edu.cn.
⁷ Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China. zhangyaguang@xjtufh.edu.cn.
⁸ High Altitude Rhinology Research Center, Eye & ENT Hospital of Fudan University and People's Hospital of Shigatse City, Shanghai, Shigatse, China. laryngeal@163.com.
⁹ ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China. laryngeal@163.com.

^# Contributed equally.

PMID: 40533675
DOI: 10.1007/s12016-025-09073-y

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory condition characterized by persistent sinus inflammation and tissue remodeling. Epithelial-derived alarmins, including thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25), are critical mediators that initiate and amplify immune responses in CRSwNP. These alarmins are secreted by stressed or damaged nasal epithelial cells in response to environmental insults, such as allergens, microbial infections, pollutants, and proteases. Once released, they orchestrate immune cell activation and amplify inflammatory pathways. Targeting epithelial-derived alarmins has emerged as a promising therapeutic strategy for CRSwNP, with several biologics, including TSLP and IL-33 inhibitors, showing encouraging clinical outcomes. This review focuses on the role of epithelial-derived alarmins in CRSwNP, examining their expression patterns, regulatory mechanisms, and contributions to inflammation, evaluating the current progress in alarmin-targeted therapies, and exploring future research directions to optimize their clinical application.

Keywords: Chronic rhinosinusitis with nasal polyps; Epithelial alarmins; IL-25; IL-33; TSLP; Type 2 inflammation.

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Conflict of interest statement

Declarations. Ethical Approval: This article is a review of previously published studies. No new studies involving human participants or animals were conducted by the authors. Competing Interests: The authors declare no competing interests.

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References

1. Stevens WW, Schleimer RP, Kern RC (2016) Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract 4(4):565–572. https://doi.org/10.1016/j.jaip.2016.04.012 - DOI - PubMed - PMC
1. Laidlaw TM, Mullol J, Woessner KM, Amin N, Mannent LP (2021) Chronic rhinosinusitis with nasal polyps and asthma. J Allergy Clin Immunol Pract 9(3):1133–1141. https://doi.org/10.1016/j.jaip.2020.09.063 - DOI - PubMed
1. Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S et al (2020) European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 58(Suppl S29):1–464. https://doi.org/10.4193/Rhin20.600
1. Hong H, Liao S, Chen F, Yang Q, Wang DY (2020) Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation. Allergy 75(11):2794–2804. https://doi.org/10.1111/all.14526 - DOI - PubMed
1. Gevaert P, Han JK, Smith SG, Sousa AR, Howarth PH, Yancey SW et al (2022) The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 12(11):1413–1423. https://doi.org/10.1002/alr.22994 - DOI - PubMed - PMC

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[1] Stevens WW, Schleimer RP, Kern RC (2016) Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract 4(4):565–572. https://doi.org/10.1016/j.jaip.2016.04.012 - DOI - PubMed - PMC

[2] Stevens WW, Schleimer RP, Kern RC (2016) Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract 4(4):565–572. https://doi.org/10.1016/j.jaip.2016.04.012 - DOI - PubMed - PMC

[3] Laidlaw TM, Mullol J, Woessner KM, Amin N, Mannent LP (2021) Chronic rhinosinusitis with nasal polyps and asthma. J Allergy Clin Immunol Pract 9(3):1133–1141. https://doi.org/10.1016/j.jaip.2020.09.063 - DOI - PubMed

[4] Laidlaw TM, Mullol J, Woessner KM, Amin N, Mannent LP (2021) Chronic rhinosinusitis with nasal polyps and asthma. J Allergy Clin Immunol Pract 9(3):1133–1141. https://doi.org/10.1016/j.jaip.2020.09.063 - DOI - PubMed

[5] Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S et al (2020) European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 58(Suppl S29):1–464. https://doi.org/10.4193/Rhin20.600

[6] Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S et al (2020) European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 58(Suppl S29):1–464. https://doi.org/10.4193/Rhin20.600

[7] Hong H, Liao S, Chen F, Yang Q, Wang DY (2020) Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation. Allergy 75(11):2794–2804. https://doi.org/10.1111/all.14526 - DOI - PubMed

[8] Hong H, Liao S, Chen F, Yang Q, Wang DY (2020) Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation. Allergy 75(11):2794–2804. https://doi.org/10.1111/all.14526 - DOI - PubMed

[9] Gevaert P, Han JK, Smith SG, Sousa AR, Howarth PH, Yancey SW et al (2022) The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 12(11):1413–1423. https://doi.org/10.1002/alr.22994 - DOI - PubMed - PMC

[10] Gevaert P, Han JK, Smith SG, Sousa AR, Howarth PH, Yancey SW et al (2022) The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 12(11):1413–1423. https://doi.org/10.1002/alr.22994 - DOI - PubMed - PMC

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Current Understanding of Epithelial-Derived Alarmins in Chronic Rhinosinusitis with Nasal Polyps

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Current Understanding of Epithelial-Derived Alarmins in Chronic Rhinosinusitis with Nasal Polyps

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