Glial-derived neurotrophic factor promotes aberrant basal cell hyperplasia in nasal polyps

  • Clin Immunol. 2025 Oct 14:281:110604. doi: 10.1016/j.clim.2025.110604.
Yilin Hou  1 ,  Lin Sun  2 ,  Mengqi Su  3 ,  Weiqiang Yang  4 ,  Lingchao Ji  4 ,  Yaqi Zhou  4 ,  Xiaochan Lu  4 ,  Na Yin  4 ,  Jiaqi Zhao  4 ,  Zihan Qiu  2 ,  Yi Wei  2 ,  Weiping Wen  2 ,  HongYi Hu  5
Affiliations
  • 1. Otorhinolaryngology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China; Department of Otorhinolaryngology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Department of Allergy, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, PR China.
  • 2. Department of Otorhinolaryngology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Department of Allergy, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, PR China.
  • 3. Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 4. Otorhinolaryngology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China.
  • 5. Otorhinolaryngology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China. Electronic address: [email protected].
PMID: 41075855 DOI: 10.1016/j.clim.2025.110604
Abstract

Background: Neurotrophins are elevated in nasal polyps (NPs) and/or allergies, exerting neurogenic inflammatory effects. Non-classical glial-derived neurotrophic factor (GDNF) family ligands (GFLs) remain poorly understood in chronic rhinosinusitis with NP (CRSwNP).

Methods: GDNF expression was analyzed in 67 nasal fluids (NFs) and 44 tissues via proteomic, transcriptomic, and immunohistochemical assays. Immunofluorescence co-staining identified GDNF and p63 + basal cells (BCs). Functional studies in human nasal epithelial cells (HNECs) assessed GDNF's affects on proliferation and barrier integrity. Bioinformatics identified regulatory networks and drug candidates.

Results: GDNF existed in NFs and tissues of CRSwNP, with higher abundance in eosinophilic NPs. P63 + BCs expression positively correlates with GDNF levels. GDNF potently activated MAPK/PI3K/Akt signaling in HNECs and induced Ki-67+/p63 + cells proliferation, while reduced distribution of claudin-1 at junctions. miR-204-5p/211-5p and two FDA-approved neuroactive drugs were predicted as GDNF modulators.

Conclusions: GDNF drives aberrant epithelial remodeling in CRSwNP via MAPK/PI3K signaling, highlighting its therapeutic potential for refractory disease.

Keywords
Glial-derived neurotrophic factor; Hyperplasia; MAPK/AKT signaling; Nasal basal cell; Nasal polyps.
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