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Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation

BACKGROUND: Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of al...

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Autores principales: Felton, Jennifer M., Lucas, Christopher D., Dorward, David A., Duffin, Rodger, Kipari, Tiina, Vermeren, Sonja, Robb, Calum T., MacLeod, Kenneth G., Serrels, Bryan, Schwarze, Jürgen, Haslett, Christopher, Dransfield, Ian, Rossi, Adriano G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mosby 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281028/
https://www.ncbi.nlm.nih.gov/pubmed/29428392
http://dx.doi.org/10.1016/j.jaci.2018.01.029
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author Felton, Jennifer M.
Lucas, Christopher D.
Dorward, David A.
Duffin, Rodger
Kipari, Tiina
Vermeren, Sonja
Robb, Calum T.
MacLeod, Kenneth G.
Serrels, Bryan
Schwarze, Jürgen
Haslett, Christopher
Dransfield, Ian
Rossi, Adriano G.
author_facet Felton, Jennifer M.
Lucas, Christopher D.
Dorward, David A.
Duffin, Rodger
Kipari, Tiina
Vermeren, Sonja
Robb, Calum T.
MacLeod, Kenneth G.
Serrels, Bryan
Schwarze, Jürgen
Haslett, Christopher
Dransfield, Ian
Rossi, Adriano G.
author_sort Felton, Jennifer M.
collection PubMed
description BACKGROUND: Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored. OBJECTIVES: In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation. METHODS: Alveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo. RESULTS: Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells. CONCLUSIONS: We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.
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spelling pubmed-62810282018-12-13 Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation Felton, Jennifer M. Lucas, Christopher D. Dorward, David A. Duffin, Rodger Kipari, Tiina Vermeren, Sonja Robb, Calum T. MacLeod, Kenneth G. Serrels, Bryan Schwarze, Jürgen Haslett, Christopher Dransfield, Ian Rossi, Adriano G. J Allergy Clin Immunol Article BACKGROUND: Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored. OBJECTIVES: In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation. METHODS: Alveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo. RESULTS: Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells. CONCLUSIONS: We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation. Mosby 2018-12 /pmc/articles/PMC6281028/ /pubmed/29428392 http://dx.doi.org/10.1016/j.jaci.2018.01.029 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Felton, Jennifer M.
Lucas, Christopher D.
Dorward, David A.
Duffin, Rodger
Kipari, Tiina
Vermeren, Sonja
Robb, Calum T.
MacLeod, Kenneth G.
Serrels, Bryan
Schwarze, Jürgen
Haslett, Christopher
Dransfield, Ian
Rossi, Adriano G.
Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
title Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
title_full Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
title_fullStr Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
title_full_unstemmed Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
title_short Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
title_sort mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281028/
https://www.ncbi.nlm.nih.gov/pubmed/29428392
http://dx.doi.org/10.1016/j.jaci.2018.01.029
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