Hypoxia disrupts the nasal epithelial barrier by inhibiting PTPN2 in chronic rhinosinusitis with nasal polyps.

Meiping Zhang, Yishan Xiong, Junhao Tu, Binxiang Tang, Zhiqiang Zhang, Jieqing Yu, Li Shen, Qing Luo, Jing Ye

International immunopharmacology 2023 May

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Hypoxia is involved in inflammation and immune response; however, its role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) is not fully understood. We aimed to investigate the mechanisms by which hypoxia disrupts the nasal epithelial barrier in CRSwNP. The expression of hypoxia-inducible factor-1α (HIF-1α), protein tyrosine phosphatase non-receptor type 2 (PTPN2), and tight junction (TJ) components (claudin-4, occludin, and ZO-1) was detected in nasal polyps using immunohistochemistry, western blotting, and qRT-PCR. Primary human nasal epithelial cells (HNECs), BEAS-2B cells, and an eosinophilic CRSwNP (Eos CRSwNP) mouse model were used to explore the potential mechanisms by which hypoxia disrupts the nasal epithelial barrier. HIF-1α expression in the non-Eos and Eos CRSwNP groups was higher than in the control group, and the expression of PTPN2 and TJs in the non-Eos and Eos CRSwNP groups were lower than those in the control group. Hypoxia decreased the expression of PTPN2 and TJs and increased epithelial cell permeability in HNECs, which was blocked by the HIF-1α inhibitor PX-478. PTPN2 overexpression inhibited hypoxia-induced downregulation of TJ expression in BEAS-2B cells, whereas PTPN2-knockdown aggravated the effects of hypoxia. In the Eos CRSwNP mouse model, both PX-478 and PTPN2 overexpression reduced the formation of nasal polypoid lesions, permeability of the nasal epithelium, and restored TJ expression. Our data indicate that hypoxia-induced HIF-1α downregulates TJ expression by inhibiting PTPN2, thereby disrupting the nasal epithelial barrier and promoting CRSwNP development. HIF-1α and PTPN2 may be potential targets for the treatment of CRSwNP. Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Meiping Zhang, Yishan Xiong, Junhao Tu, Binxiang Tang, Zhiqiang Zhang, Jieqing Yu, Li Shen, Qing Luo, Jing Ye. Hypoxia disrupts the nasal epithelial barrier by inhibiting PTPN2 in chronic rhinosinusitis with nasal polyps. International immunopharmacology. 2023 May;118:110054