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

K. M. Hudock; M. S. Collins; M. A. Imbrogno; E. L. Kramer; J. J. Brewington; A. Ziady; N. Zhang; J. Snowball; Y. Xu; B. C. Carey; Y. Horio; 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; N. Mangalmurti; B. C. Trapnell; J. P. Clancy

doi:10.3389/fimmu.2022.1023553

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

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

Animal Science

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

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.

Original language	English (US)
Article number	1023553
Journal	Frontiers in immunology
Volume	13
DOIs	https://doi.org/10.3389/fimmu.2022.1023553
State	Published - Jan 10 2023

Bibliographical note

Funding Information:
NIH NHLBI 1K08HL124191, CFF K Boost HUDOCK20, NIH NHLBI K08HL124191-04S1, RDP CCHMC, Cystic Fibrosis Foundation, Parker B Francis Fellowship, CFF NAREN19R0, UC Department of Medicine Impact Award, NIH HL148856 and NIH HL153045. Acknowledgments

Publisher Copyright:
Copyright © 2023 Hudock, Collins, Imbrogno, Kramer, Brewington, Ziady, Zhang, Snowball, Xu, Carey, Horio, O’Grady, Kopras, Meeker, Morgan, Ostmann, Skala, Siefert, Na, Davidson, Gollomp, Mangalmurti, Trapnell and Clancy.

Keywords

E-cadherin (CDH1)
NETs (neutrophil extracellular traps)
alpha-1 antitrypsin (A1AT)
barrier function
bronchial epithelia

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fimmu.2022.1023553

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Hudock, K. M., Collins, M. S., Imbrogno, M. A., Kramer, E. L., Brewington, J. J., Ziady, A., Zhang, N., Snowball, J., Xu, Y., Carey, B. C., Horio, Y., O’Grady, S. M., Kopras, E. J., Meeker, J., Morgan, H., Ostmann, A. J., Skala, E., Siefert, M. E., Na, C. L., ... Clancy, J. P. (2023). Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function. Frontiers in immunology, 13, Article 1023553. https://doi.org/10.3389/fimmu.2022.1023553

Hudock, KM, Collins, MS, Imbrogno, MA, Kramer, EL, Brewington, JJ, Ziady, A, Zhang, N, Snowball, J, Xu, Y, Carey, BC, Horio, Y, O’Grady, SM, Kopras, EJ, Meeker, J, Morgan, H, Ostmann, AJ, Skala, E, Siefert, ME, Na, CL, Davidson, CR, Gollomp, K, Mangalmurti, N, Trapnell, BC & Clancy, JP 2023, 'Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function', Frontiers in immunology, vol. 13, 1023553. https://doi.org/10.3389/fimmu.2022.1023553

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title = "Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function",

abstract = "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.",

keywords = "E-cadherin (CDH1), NETs (neutrophil extracellular traps), alpha-1 antitrypsin (A1AT), barrier function, bronchial epithelia",

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

note = "Funding Information: NIH NHLBI 1K08HL124191, CFF K Boost HUDOCK20, NIH NHLBI K08HL124191-04S1, RDP CCHMC, Cystic Fibrosis Foundation, Parker B Francis Fellowship, CFF NAREN19R0, UC Department of Medicine Impact Award, NIH HL148856 and NIH HL153045. Acknowledgments Publisher Copyright: Copyright {\textcopyright} 2023 Hudock, Collins, Imbrogno, Kramer, Brewington, Ziady, Zhang, Snowball, Xu, Carey, Horio, O{\textquoteright}Grady, Kopras, Meeker, Morgan, Ostmann, Skala, Siefert, Na, Davidson, Gollomp, Mangalmurti, Trapnell and Clancy.",

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doi = "10.3389/fimmu.2022.1023553",

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T1 - Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function

AU - Hudock, K. M.

AU - Collins, M. S.

AU - Imbrogno, M. A.

AU - Kramer, E. L.

AU - Brewington, J. J.

AU - Ziady, A.

AU - Zhang, N.

AU - Snowball, J.

AU - Xu, Y.

AU - Carey, B. C.

AU - Horio, Y.

AU - O’Grady, S. M.

AU - Kopras, E. J.

AU - Meeker, J.

AU - Morgan, H.

AU - Ostmann, A. J.

AU - Skala, E.

AU - Siefert, M. E.

AU - Na, C. L.

AU - Davidson, C. R.

AU - Gollomp, K.

AU - Mangalmurti, N.

AU - Trapnell, B. C.

AU - Clancy, J. P.

N1 - Funding Information: NIH NHLBI 1K08HL124191, CFF K Boost HUDOCK20, NIH NHLBI K08HL124191-04S1, RDP CCHMC, Cystic Fibrosis Foundation, Parker B Francis Fellowship, CFF NAREN19R0, UC Department of Medicine Impact Award, NIH HL148856 and NIH HL153045. Acknowledgments Publisher Copyright: Copyright © 2023 Hudock, Collins, Imbrogno, Kramer, Brewington, Ziady, Zhang, Snowball, Xu, Carey, Horio, O’Grady, Kopras, Meeker, Morgan, Ostmann, Skala, Siefert, Na, Davidson, Gollomp, Mangalmurti, Trapnell and Clancy.

PY - 2023/1/10

Y1 - 2023/1/10

N2 - 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.

AB - 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.

KW - E-cadherin (CDH1)

KW - NETs (neutrophil extracellular traps)

KW - alpha-1 antitrypsin (A1AT)

KW - barrier function

KW - bronchial epithelia

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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