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

Autor: Liegeois MA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA., Braunreuther M; Department of Chemical Engineering, Stanford University, Stanford, California, USA., Charbit AR; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA., Raymond WW; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA., Tang M; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA., Woodruff PG; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA., Christenson SA; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA., Castro M; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA., Erzurum SC; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Israel E; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA., Jarjour NN; Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Levy BD; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA., Moore WC; Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Wenzel SE; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Fuller GG; Department of Chemical Engineering, Stanford University, Stanford, California, USA., Fahy JV; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UCSF, San Francisco, California, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Jun 18; Vol. 9 (15). Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1172/jci.insight.181024
Abstrakt: 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.
Databáze: MEDLINE