Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke

Introduction/Rationale: In chronic obstructive pulmonary disease (COPD), defective macrophage phagocytic clearance of cells undergoing apoptosis by efferocytosis may lead to secondary necrosis of the uncleared cells and contribute to airway inflammation. The precise mechanisms for this phenomenon re...

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Autores principales:	Patrick F. Asare, Hai B. Tran, Plinio R. Hurtado, Griffith B. Perkins, Phan Nguyen, Hubertus Jersmann, Eugene Roscioli, Sandra Hodge
Formato:	article
Lenguaje:	EN
Publicado:	SAGE Publishing 2021
Materias:	Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/dbd46a76f302486c98c0d1a21e6b7af5
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spelling	oai:doaj.org-article:dbd46a76f302486c98c0d1a21e6b7af52021-12-02T23:33:26ZInhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke1753-466610.1177/17534666211039769https://doaj.org/article/dbd46a76f302486c98c0d1a21e6b7af52021-10-01T00:00:00Zhttps://doi.org/10.1177/17534666211039769https://doaj.org/toc/1753-4666Introduction/Rationale: In chronic obstructive pulmonary disease (COPD), defective macrophage phagocytic clearance of cells undergoing apoptosis by efferocytosis may lead to secondary necrosis of the uncleared cells and contribute to airway inflammation. The precise mechanisms for this phenomenon remain unknown. LC3-associated phagocytosis (LAP) is indispensable for effective efferocytosis. We hypothesized that cigarette smoke inhibits the regulators of LAP pathway, potentially contributing to the chronic airways inflammation associated with COPD. Methods: Bronchoalveolar (BAL)-derived alveolar macrophages, lung tissue macrophages obtained from lung resection surgery, and monocyte-derived macrophages (MDM) were prepared from COPD patients and control participants. Lung/airway samples from mice chronically exposed to cigarette smoke were also investigated. Differentiated THP-1 cells were exposed to cigarette smoke extract (CSE). The LAP pathway including Rubicon, as an essential regulator of LAP, efferocytosis and inflammation was examined using western blot, ELISA, flow cytometry, and/or immunofluorescence. Results: Rubicon was significantly depleted in COPD alveolar macrophages compared with non-COPD control macrophages. Rubicon protein in alveolar macrophages of cigarette smoke-exposed mice and cigarette smoke-exposed MDM and THP-1 was decreased with a concomitant impairment of efferocytosis. We also noted increased expression of LC3 which is critical for LAP pathway in COPD and THP-1 macrophages. Furthermore, THP-1 macrophages exposed to cigarette smoke extract exhibited higher levels of other key components of LAP pathway including Atg5 and TIM-4. There was a strong positive correlation between Rubicon protein expression and efferocytosis. Conclusion: LAP is a requisite for effective efferocytosis and an appropriate inflammatory response, which is impaired by Rubicon deficiency. Our findings suggest dysregulated LAP due to reduced Rubicon as a result of CSE exposure. This phenomenon could lead to a failure of macrophages to effectively process phagosomes containing apoptotic cells during efferocytosis. Restoring Rubicon protein expression has unrecognized therapeutic potential in the context of disease-related modifications caused by exposure to cigarette smoke.Patrick F. AsareHai B. TranPlinio R. HurtadoGriffith B. PerkinsPhan NguyenHubertus JersmannEugene RoscioliSandra HodgeSAGE PublishingarticleDiseases of the respiratory systemRC705-779ENTherapeutic Advances in Respiratory Disease, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the respiratory system RC705-779
spellingShingle	Diseases of the respiratory system RC705-779 Patrick F. Asare Hai B. Tran Plinio R. Hurtado Griffith B. Perkins Phan Nguyen Hubertus Jersmann Eugene Roscioli Sandra Hodge Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke
description	Introduction/Rationale: In chronic obstructive pulmonary disease (COPD), defective macrophage phagocytic clearance of cells undergoing apoptosis by efferocytosis may lead to secondary necrosis of the uncleared cells and contribute to airway inflammation. The precise mechanisms for this phenomenon remain unknown. LC3-associated phagocytosis (LAP) is indispensable for effective efferocytosis. We hypothesized that cigarette smoke inhibits the regulators of LAP pathway, potentially contributing to the chronic airways inflammation associated with COPD. Methods: Bronchoalveolar (BAL)-derived alveolar macrophages, lung tissue macrophages obtained from lung resection surgery, and monocyte-derived macrophages (MDM) were prepared from COPD patients and control participants. Lung/airway samples from mice chronically exposed to cigarette smoke were also investigated. Differentiated THP-1 cells were exposed to cigarette smoke extract (CSE). The LAP pathway including Rubicon, as an essential regulator of LAP, efferocytosis and inflammation was examined using western blot, ELISA, flow cytometry, and/or immunofluorescence. Results: Rubicon was significantly depleted in COPD alveolar macrophages compared with non-COPD control macrophages. Rubicon protein in alveolar macrophages of cigarette smoke-exposed mice and cigarette smoke-exposed MDM and THP-1 was decreased with a concomitant impairment of efferocytosis. We also noted increased expression of LC3 which is critical for LAP pathway in COPD and THP-1 macrophages. Furthermore, THP-1 macrophages exposed to cigarette smoke extract exhibited higher levels of other key components of LAP pathway including Atg5 and TIM-4. There was a strong positive correlation between Rubicon protein expression and efferocytosis. Conclusion: LAP is a requisite for effective efferocytosis and an appropriate inflammatory response, which is impaired by Rubicon deficiency. Our findings suggest dysregulated LAP due to reduced Rubicon as a result of CSE exposure. This phenomenon could lead to a failure of macrophages to effectively process phagosomes containing apoptotic cells during efferocytosis. Restoring Rubicon protein expression has unrecognized therapeutic potential in the context of disease-related modifications caused by exposure to cigarette smoke.
format	article
author	Patrick F. Asare Hai B. Tran Plinio R. Hurtado Griffith B. Perkins Phan Nguyen Hubertus Jersmann Eugene Roscioli Sandra Hodge
author_facet	Patrick F. Asare Hai B. Tran Plinio R. Hurtado Griffith B. Perkins Phan Nguyen Hubertus Jersmann Eugene Roscioli Sandra Hodge
author_sort	Patrick F. Asare
title	Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke
title_short	Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke
title_full	Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke
title_fullStr	Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke
title_full_unstemmed	Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke
title_sort	inhibition of lc3-associated phagocytosis in copd and in response to cigarette smoke
publisher	SAGE Publishing
publishDate	2021
url	https://doaj.org/article/dbd46a76f302486c98c0d1a21e6b7af5
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Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke

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