Autophagy of mucin granules contributes to resolution of airway mucous metaplasia

Abstract 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...

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Autores principales:	J. M. Sweeter, K. Kudrna, K. Hunt, P. Thomes, B. F. Dickey, S. L. Brody, J. D. Dickinson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7f49a740466d41f8a933737ae52f1e82
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spelling	oai:doaj.org-article:7f49a740466d41f8a933737ae52f1e822021-12-02T18:02:54ZAutophagy of mucin granules contributes to resolution of airway mucous metaplasia10.1038/s41598-021-91932-72045-2322https://doaj.org/article/7f49a740466d41f8a933737ae52f1e822021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91932-7https://doaj.org/toc/2045-2322Abstract 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.J. M. SweeterK. KudrnaK. HuntP. ThomesB. F. DickeyS. L. BrodyJ. D. DickinsonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q J. M. Sweeter K. Kudrna K. Hunt P. Thomes B. F. Dickey S. L. Brody J. D. Dickinson Autophagy of mucin granules contributes to resolution of airway mucous metaplasia
description	Abstract 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.
format	article
author	J. M. Sweeter K. Kudrna K. Hunt P. Thomes B. F. Dickey S. L. Brody J. D. Dickinson
author_facet	J. M. Sweeter K. Kudrna K. Hunt P. Thomes B. F. Dickey S. L. Brody J. D. Dickinson
author_sort	J. M. Sweeter
title	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_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_sort	autophagy of mucin granules contributes to resolution of airway mucous metaplasia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7f49a740466d41f8a933737ae52f1e82
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Autophagy of mucin granules contributes to resolution of airway mucous metaplasia

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