Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi
Abstract Background Non-typeable Haemophilus influenza (NTHi) infection is common in COPD. Corticosteroids can have limited therapeutic effects in COPD patients. NTHi causes corticosteroid insensitive cytokine production from COPD alveolar macrophages. We investigated the mechanisms by which NTHi ca...
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doaj-09b47fcdd96e4fa1a53d1c199555dff02020-11-24T21:33:54ZengBMCRespiratory Research1465-993X2017-04-0118111010.1186/s12931-017-0539-4Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHiRana M. Khalaf0Simon R. Lea1Hannah J. Metcalfe2Dave Singh3The University of Manchester, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation TrustThe University of Manchester, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation TrustThe University of Manchester, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation TrustThe University of Manchester, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation TrustAbstract Background Non-typeable Haemophilus influenza (NTHi) infection is common in COPD. Corticosteroids can have limited therapeutic effects in COPD patients. NTHi causes corticosteroid insensitive cytokine production from COPD alveolar macrophages. We investigated the mechanisms by which NTHi causes corticosteroid insensitive inflammatory responses, and the effects of NTHi exposure on COPD macrophage polarisation. Method Alveolar macrophages from COPD patients and controls were exposed to NTHi in conjunction with the corticosteroid dexamethasone and/or the p38 MAPK inhibitor BIRB-796. Cytokine release, GR phosphorylation and modulation and macrophage phenotype were analysed. Results Dexamethasone significantly inhibited NTHi induced TNF-α, IL-6 and IL-10 from COPD macrophages but, CXCL8 was not suppressed. BIRB-796 combined with dexamethasone caused significantly greater inhibition of all cytokines than either drug alone (p < 0.05 all comparisons). NTHi caused phosphorylation of GR S226 reducing GR nuclear localisation, an effect regulated by p38 MAPK. NTHi altered macrophage polarisation by increasing IL-10 and decreasing CD36, CD206, CD163 and HLA-DR. Conclusion NTHi exposure causes p38 MAPK dependent GR phosphorylation associated with decreased GR function in COPD alveolar macrophages. Combining a p38 MAPK inhibitor with corticosteroids can enhance anti-inflammatory effects during NTHi exposure of COPD alveolar macrophages. NTHi causes macrophage polarisation that favours bacterial persistence.http://link.springer.com/article/10.1186/s12931-017-0539-4Chronic Obstructive Pulmonary DiseaseGlucocorticoid ReceptorChronic Obstructive Pulmonary Disease PatientAlveolar MacrophageMacrophage Polarisation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rana M. Khalaf Simon R. Lea Hannah J. Metcalfe Dave Singh |
spellingShingle |
Rana M. Khalaf Simon R. Lea Hannah J. Metcalfe Dave Singh Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi Respiratory Research Chronic Obstructive Pulmonary Disease Glucocorticoid Receptor Chronic Obstructive Pulmonary Disease Patient Alveolar Macrophage Macrophage Polarisation |
author_facet |
Rana M. Khalaf Simon R. Lea Hannah J. Metcalfe Dave Singh |
author_sort |
Rana M. Khalaf |
title |
Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi |
title_short |
Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi |
title_full |
Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi |
title_fullStr |
Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi |
title_full_unstemmed |
Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi |
title_sort |
mechanisms of corticosteroid insensitivity in copd alveolar macrophages exposed to nthi |
publisher |
BMC |
series |
Respiratory Research |
issn |
1465-993X |
publishDate |
2017-04-01 |
description |
Abstract Background Non-typeable Haemophilus influenza (NTHi) infection is common in COPD. Corticosteroids can have limited therapeutic effects in COPD patients. NTHi causes corticosteroid insensitive cytokine production from COPD alveolar macrophages. We investigated the mechanisms by which NTHi causes corticosteroid insensitive inflammatory responses, and the effects of NTHi exposure on COPD macrophage polarisation. Method Alveolar macrophages from COPD patients and controls were exposed to NTHi in conjunction with the corticosteroid dexamethasone and/or the p38 MAPK inhibitor BIRB-796. Cytokine release, GR phosphorylation and modulation and macrophage phenotype were analysed. Results Dexamethasone significantly inhibited NTHi induced TNF-α, IL-6 and IL-10 from COPD macrophages but, CXCL8 was not suppressed. BIRB-796 combined with dexamethasone caused significantly greater inhibition of all cytokines than either drug alone (p < 0.05 all comparisons). NTHi caused phosphorylation of GR S226 reducing GR nuclear localisation, an effect regulated by p38 MAPK. NTHi altered macrophage polarisation by increasing IL-10 and decreasing CD36, CD206, CD163 and HLA-DR. Conclusion NTHi exposure causes p38 MAPK dependent GR phosphorylation associated with decreased GR function in COPD alveolar macrophages. Combining a p38 MAPK inhibitor with corticosteroids can enhance anti-inflammatory effects during NTHi exposure of COPD alveolar macrophages. NTHi causes macrophage polarisation that favours bacterial persistence. |
topic |
Chronic Obstructive Pulmonary Disease Glucocorticoid Receptor Chronic Obstructive Pulmonary Disease Patient Alveolar Macrophage Macrophage Polarisation |
url |
http://link.springer.com/article/10.1186/s12931-017-0539-4 |
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