Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function

K. M. Hudock; K. M. Hudock; K. M. Hudock; M. S. Collins; M. A. Imbrogno; E. L. Kramer; E. L. Kramer; J. J. Brewington; J. J. Brewington; A. Ziady; A. Ziady; N. Zhang; N. Zhang; J. Snowball; Y. Xu; Y. Xu; Y. Xu; B. C. Carey; B. C. Carey; Y. Horio; Y. Horio; S. M. O’Grady; S. M. O’Grady; E. J. Kopras; J. Meeker; H. Morgan; A. J. Ostmann; E. Skala; M. E. Siefert; C. L. Na; C. R. Davidson; K. Gollomp; K. Gollomp; N. Mangalmurti; N. Mangalmurti; B. C. Trapnell; B. C. Trapnell; B. C. Trapnell; J. P. Clancy

doi:10.3389/fimmu.2022.1023553

Frontiers in Immunology (Jan 2023)

Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function

K. M. Hudock,
K. M. Hudock,
K. M. Hudock,
M. S. Collins,
M. A. Imbrogno,
E. L. Kramer,
E. L. Kramer,
J. J. Brewington,
J. J. Brewington,
A. Ziady,
A. Ziady,
N. Zhang,
N. Zhang,
J. Snowball,
Y. Xu,
Y. Xu,
Y. Xu,
B. C. Carey,
B. C. Carey,
Y. Horio,
Y. Horio,
S. M. O’Grady,
S. M. O’Grady,
E. J. Kopras,
J. Meeker,
H. Morgan,
A. J. Ostmann,
E. Skala,
M. E. Siefert,
C. L. Na,
C. R. Davidson,
K. Gollomp,
K. Gollomp,
N. Mangalmurti,
N. Mangalmurti,
B. C. Trapnell,
B. C. Trapnell,
B. C. Trapnell,
J. P. Clancy

Affiliations

K. M. Hudock: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
K. M. Hudock: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
K. M. Hudock: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
M. S. Collins: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
M. A. Imbrogno: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
E. L. Kramer: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
E. L. Kramer: Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
J. J. Brewington: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
J. J. Brewington: Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
A. Ziady: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
A. Ziady: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
N. Zhang: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
N. Zhang: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
J. Snowball: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Y. Xu: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Y. Xu: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
Y. Xu: Divisions of Biomedical Informatics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
B. C. Carey: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
B. C. Carey: Translational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Y. Horio: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Y. Horio: Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto-shi, Kumamoto, Japan
S. M. O’Grady: 0Departments of Animal Science, University of Minnesota, St. Paul, MN, United States
S. M. O’Grady: 1Department of Integrative Biology and Physiology, University of Minnesota, St. Paul, MN, United States
E. J. Kopras: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
J. Meeker: Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
H. Morgan: Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
A. J. Ostmann: Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
E. Skala: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
M. E. Siefert: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
C. L. Na: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
C. R. Davidson: Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
K. Gollomp: 2Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
K. Gollomp: 3Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
N. Mangalmurti: 4Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
N. Mangalmurti: 5Pennsylvania Lung Biology Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
B. C. Trapnell: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
B. C. Trapnell: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
B. C. Trapnell: Translational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
J. P. Clancy: 6Cystic Fibrosis Foundation, Bethesda, MD, United States

DOI: https://doi.org/10.3389/fimmu.2022.1023553
Journal volume & issue: Vol. 13

Abstract

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Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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