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Autophagy of mucin granules contributes to resolution of airway mucous metaplasia

Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous metaplasia (MM). Many molecular pathways triggering MM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the...

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Autores principales: Sweeter, J. M., Kudrna, K., Hunt, K., Thomes, P., Dickey, B. F., Brody, S. L., Dickinson, J. D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219712/
https://www.ncbi.nlm.nih.gov/pubmed/34158522
http://dx.doi.org/10.1038/s41598-021-91932-7
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author Sweeter, J. M.
Kudrna, K.
Hunt, K.
Thomes, P.
Dickey, B. F.
Brody, S. L.
Dickinson, J. D.
author_facet Sweeter, J. M.
Kudrna, K.
Hunt, K.
Thomes, P.
Dickey, B. F.
Brody, S. L.
Dickinson, J. D.
author_sort Sweeter, J. M.
collection PubMed
description Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous metaplasia (MM). Many molecular pathways triggering MM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagy pathway is required for resolution of MM by eliminating excess non-secreted intracellular mucin granules. We found increased intracellular levels of mucins Muc5ac and Muc5b in mice deficient in autophagy regulatory protein, Atg16L1, and that this difference was not due to defects in the known baseline or stimulated mucin secretion pathways. Instead, we found that, in mucous secretory cells, Lc3/Lamp1 vesicles colocalized with mucin granules particularly adjacent to the nucleus, suggesting that some granules were being eliminated in the autophagy pathway rather than secreted. Using a mouse model of MM resolution, we found increased lysosomal proteolytic activity that peaked in the days after mucin production began to decline. In purified lysosomal fractions, Atg16L1-deficient mice had reduced proteolytic degradation of Lc3 and Sqstm1 and persistent accumulation of mucin granules associated with impaired resolution of mucous metaplasia. In normal and COPD derived human airway epithelial cells (AECs), activation of autophagy by mTOR inhibition led to a reduction of intracellular mucin granules in AECs. Our findings indicate that during peak and resolution phases of MM, autophagy activity rather than secretion is required for elimination of some remaining mucin granules. Manipulation of autophagy activation offers a therapeutic target to speed resolution of MM in airway disease exacerbations.
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spelling pubmed-82197122021-06-24 Autophagy of mucin granules contributes to resolution of airway mucous metaplasia Sweeter, J. M. Kudrna, K. Hunt, K. Thomes, P. Dickey, B. F. Brody, S. L. Dickinson, J. D. Sci Rep Article Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous metaplasia (MM). Many molecular pathways triggering MM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagy pathway is required for resolution of MM by eliminating excess non-secreted intracellular mucin granules. We found increased intracellular levels of mucins Muc5ac and Muc5b in mice deficient in autophagy regulatory protein, Atg16L1, and that this difference was not due to defects in the known baseline or stimulated mucin secretion pathways. Instead, we found that, in mucous secretory cells, Lc3/Lamp1 vesicles colocalized with mucin granules particularly adjacent to the nucleus, suggesting that some granules were being eliminated in the autophagy pathway rather than secreted. Using a mouse model of MM resolution, we found increased lysosomal proteolytic activity that peaked in the days after mucin production began to decline. In purified lysosomal fractions, Atg16L1-deficient mice had reduced proteolytic degradation of Lc3 and Sqstm1 and persistent accumulation of mucin granules associated with impaired resolution of mucous metaplasia. In normal and COPD derived human airway epithelial cells (AECs), activation of autophagy by mTOR inhibition led to a reduction of intracellular mucin granules in AECs. Our findings indicate that during peak and resolution phases of MM, autophagy activity rather than secretion is required for elimination of some remaining mucin granules. Manipulation of autophagy activation offers a therapeutic target to speed resolution of MM in airway disease exacerbations. Nature Publishing Group UK 2021-06-22 /pmc/articles/PMC8219712/ /pubmed/34158522 http://dx.doi.org/10.1038/s41598-021-91932-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sweeter, J. M.
Kudrna, K.
Hunt, K.
Thomes, P.
Dickey, B. F.
Brody, S. L.
Dickinson, J. D.
Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
title Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
title_full Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
title_fullStr Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
title_full_unstemmed Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
title_short Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
title_sort autophagy of mucin granules contributes to resolution of airway mucous metaplasia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219712/
https://www.ncbi.nlm.nih.gov/pubmed/34158522
http://dx.doi.org/10.1038/s41598-021-91932-7
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