Hypoxia induces the production of epithelial-derived cytokines in eosinophilic chronic rhinosinusitis with nasal polyps

  • Int Immunopharmacol. 2023 Jun 24;121:110559. doi: 10.1016/j.intimp.2023.110559.
Meiping Zhang  1 ,  Binxiang Tang  1 ,  Ligui Huang  2 ,  Yishan Xiong  3 ,  Junhao Tu  3 ,  Yizhen Jia  3 ,  Fan Jiang  3 ,  Li Shen  3 ,  Qing Luo  3 ,  Jing Ye  4
Affiliations
  • 1. Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; Institute of Jiangxi Otorhinolaryngology Head & Neck Suegery, Nanchang, Jiangxi Province, China.
  • 2. The 908th Hospital of Joint Logistics Support Force of PLA, Nanchang, Jiangxi Province, China.
  • 3. Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
  • 4. Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; Institute of Jiangxi Otorhinolaryngology Head & Neck Suegery, Nanchang, Jiangxi Province, China. Electronic address: [email protected].
PMID: 37364325 DOI: 10.1016/j.intimp.2023.110559
Abstract

Background: Hypoxia plays a significant role in the pathogenesis of chronic rhinosinusitis (CRS). However, the role and mechanism of hypoxia in the type 2 immune response in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remain unclear.

Methods: The expression of hypoxia-inducible factor-1α (HIF-1α) and epithelial-derived cytokines (EDCs), including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), was detected in nasal polyps via immunohistochemical analysis. The relationship between HIF-1α and EDCs was also elucidated using Pearson's correlation. Moreover, primary human nasal epithelial cells (HNECs) and a mouse model of ECRSwNP were employed to elucidate the role and mechanism of hypoxia in type 2 immune responses.

Results: HIF-1α, IL-25, IL-33, and TSLP expression levels were upregulated in the non-ECRSwNP and ECRSwNP groups compared with the control group, with the ECRSwNP group having the highest HIF-1α and EDC expression levels. Additionally, HIF-1α was positively correlated with IL-25 and IL-33 in the ECRSwNP group. Meanwhile, treatment with a HIF-1α Inhibitor, PX-478, inhibited the hypoxia-induced increase in the mRNA and protein expression of EDCs and type 2 cytokines in HNECs. Similarly, in vivo, PX-478 inhibited EDC expression in the sinonasal mucosa of mice with ECRSwNP.

Conclusions: Hypoxia induces EDC expression by upregulating HIF-1α levels, thereby promoting type 2 immune responses and the development of ECRSwNP. Hence, targeting HIF-1α may represent an effective therapeutic strategy for ECRSwNP.

Keywords
Eosinophilic chronic rhinosinusitis with nasal polyps; Epithelial-derived cytokines; Hypoxia; Hypoxia-inducible factor-1α; Type 2 immune response.
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