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TMEM16A-Mediated Mucin Secretion in IL-13-Induced Nasal Epithelial Cells From Chronic Rhinosinusitis Patients
Yu Zhang1, Xiangdong Wang2, Hong Wang3
1Department of Otolaryngology, Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Purpose:
Chronic rhinosinusitis with nasal polyps (CRSwNP), a mainly Th2 cytokine-mediated disease, often involves mucus secretion. Recent evidence suggests that transmembrane protein 16A (TMEM16A), a calcium-activated Cl- channel (CaCC), can regulate mucus secretion from airway epithelium by transepithelial electrolyte transport and hydration. However, the role of TMEM16A in mucin production/secretion in the airway epithelium is not clear. This study was conducted to determine the role of TMEM16A in mediating mucin secretion in human nasal polyp epithelial cells (HNPECs) induced by IL-13.
Methods:
Human sinonasal mucosa tissue and dissociated sinonasal epithelium from control subjects and patients with CRSwNP were assessed for the expression of TMEM16A and the secretion of human mucin 5AC (MUC5AC) by immunohistochemistry, Western blot analysis, and enzyme-linked immuno-sorbent assay (ELISA). A model of the Th2 inflammatory environment was created by exposure of primary air-liquid interface (ALI)-cultured HNPECs to interleukin-13 (IL-13) for 14 days, with subsequent assessment of TMEM16A expression in cell lysates by Western blotting and MUC5AC secretion in apical washings of cells by ELISA.
Results:
The expressions of TMEM16A and MUC5AC were increased in human nasal polyp tissue and dissociated nasal polyp epithelium. TMEM16A was detected in IL-13-treated HNPECs, specifically in MUC5AC-positive cells but not in ciliated cells. IL-13 treatment increased percentages of TMEM16A-positive cells, MUC5AC-positive cells, and cells coexpressing TMEM16A/MUC5AC, the expression of TMEM16A protein, and the secretion of MUC5AC. T16Ainh-A01, a TMEM16A inhibitor, attenuated these IL-13-induced effects.
Conclusions:
The expression of TMEM16A and MUC5AC are increased in CRSwNP, which might be a direct effect of Th2 cytokines present in the sinonasal mucosa in CRSwNP. Down-regulation of TMEM16A expression and MUC5AC secretion in HNPECs by T16Ainh-A01 indicates that TMEM16A might play an important role in mucin secretion in upper airway inflammatory diseases.
Insights
Transmembrane protein 16A (TMEM16A) and mucin 5AC (MUC5AC) are elevated in chronic rhinosinusitis with nasal polyps. TMEM16A inhibition reduced MUC5AC secretion, suggesting TMEM16A’s role in airway mucus production.
Area of Science:
- Respiratory Medicine
- Molecular Biology
- Immunology
Background:
- Chronic rhinosinusitis with nasal polyps (CRSwNP) is a Th2-mediated disease characterized by mucus hypersecretion.
- Transmembrane protein 16A (TMEM16A), a calcium-activated chloride channel (CaCC), is implicated in airway epithelial electrolyte transport and hydration, potentially influencing mucus secretion.
- The specific role of TMEM16A in regulating mucin production and secretion in CRSwNP remains unclear.
Purpose of the Study:
- To investigate the role of TMEM16A in mediating mucin secretion in human nasal polyp epithelial cells (HNPECs) stimulated by interleukin-13 (IL-13).
Main Methods:
- Assessed TMEM16A and MUC5AC expression and secretion in sinonasal tissues and primary HNPECs using immunohistochemistry, Western blot, and ELISA.
- Induced a Th2 inflammatory environment in air-liquid interface (ALI)-cultured HNPECs with IL-13.
- Evaluated the effect of a TMEM16A inhibitor (T16Ainh-A01) on IL-13-induced responses.
Main Results:
- TMEM16A and MUC5AC expression were significantly increased in nasal polyp tissues and HNPECs from CRSwNP patients.
- IL-13 treatment upregulated TMEM16A and MUC5AC expression and MUC5AC secretion in HNPECs, with TMEM16A localized to MUC5AC-positive cells.
- Inhibition of TMEM16A by T16Ainh-A01 attenuated the IL-13-induced increase in MUC5AC secretion.
Conclusions:
- Elevated TMEM16A and MUC5AC expression in CRSwNP may be a direct consequence of Th2 cytokine activity.
- TMEM16A plays a significant role in regulating mucin secretion in the upper airway epithelium during inflammatory conditions like CRSwNP.
- Targeting TMEM16A could be a potential therapeutic strategy for managing excessive mucus production in CRSwNP.
