Journal Article

Peroxidase-mediated mucin cross-linking drives pathologic mucus gel formation in IL-13-stimulated airway epithelial cells

Liegeois, Maude A., Charbit, Annabelle R., Wenzel, Sally E., Fahy, John V., Castro, Mario, Braunreuther, Margaret, Israel, Elliot, Raymond, Wilfred W., Christenson, Stephanie A., Tang, Monica, Moore, Wendy C., Erzurum, Serpil C., Woodruff, Prescott G., Jarjour, Nizar N., Fuller, Gerald G., Levy, Bruce D.

2024

Overview

Mucus plugs occlude airways to obstruct airflow in asthma. Studies in patients and in mouse models show that mucus plugs occur in the context of type 2 inflammation, and studies in human airway epithelial cells (HAECs) show that IL-13-activated cells generate pathologic mucus independently of immune cells. To determine how HAECs autonomously generate pathologic mucus, we used a magnetic microwire rheometer to characterize the viscoelastic properties of mucus secreted under varying conditions. We found that normal HAEC mucus exhibited viscoelastic liquid behavior and that mucus secreted by IL-13-activated HAECs exhibited solid-like behavior caused by mucin cross-linking. In addition, IL-13-activated HAECs shows increased peroxidase activity in apical secretions, and an overlaid thiolated polymer (thiomer) solution shows an increase in solid behavior that was prevented by peroxidase inhibition. Furthermore, gene expression for thyroid peroxidase (TPO), but not lactoperoxidase (LPO), was increased in IL-13-activated HAECs and both TPO and LPO catalyze the formation of oxidant acids that cross-link thiomer solutions. Finally, gene expression for TPO in airway epithelial brushings was increased in patients with asthma with high airway mucus plug scores. Together, our results show that IL-13-activated HAECs autonomously generated pathologic mucus via peroxidase-mediated cross-linking of mucin polymers.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Animal models / Asthma / Asthma - metabolism / Asthma - pathology / Cell biology / Compliance / Epithelial Cells / Epithelial Cells - metabolism / Gels / Gene expression / Human health sciences / Humans / IL13 protein, human / Immunologie & maladie infectieuse / Immunology & infectious disease / Interleukin 13 / Interleukin-13 - metabolism / Interleukin-13 - pharmacology / Iodide peroxidase / Lactoperoxidase / Lactoperoxidase - metabolism / Medicine (all) / Molecular biology / Mucin / Mucins / Mucins - metabolism / Mucus / Mucus - metabolism / Oxidants / Pulmonology / Respiratory Mucosa / Respiratory Mucosa - metabolism / Respiratory Mucosa - pathology / Respiratory tract / Sciences de la santé humaine / Th2 response / Viscoelasticity / Viscosity