RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD
Allergy, vol. 76, pp. 1123–1135
Abstract
Abstract Background The receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. Methods We measured airway inflammation and AHR in wild‐type, RAGE −/− , TLR4 −/− and TLR4 −/− RAGE −/− mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. Results RAGE −/− mice were protected against CS‐induced neutrophilia and AHR. In contrast, TLR4 −/− mice were not protected against CS‐induced neutrophilia and had more severe CS‐induced AHR. TLR4 −/− RAGE −/− mice were not protected against CS‐induced neutrophilia but were partially protected against CS‐induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. Conclusions Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.
Authors 17
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University of Technology Sydney
Affiliation as printed
Graduate School of Health Faculty of Health The University of Technology Sydney Ultimo NSW Australia
Graduate School of Health, Faculty of Health, The University of Technology Sydney, Ultimo, NSW, Australia
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University of Technology Sydney · University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
School of Life Sciences Faculty of Science The University of Technology Sydney Ultimo NSW Australia
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
School of Life Sciences, Faculty of Science, The University of Technology Sydney, Ultimo, NSW, Australia
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Affiliation as printed
Biomedicine Discovery Institute and Department of Pharmacology School of Biomedical Sciences Monash University Melbourne Vic. Australia
Biomedicine Discovery Institute and Department of Pharmacology, School of Biomedical Sciences, Monash University, Melbourne, Vic., Australia
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University of Technology Sydney
Affiliation as printed
School of Life Sciences Faculty of Science The University of Technology Sydney Ultimo NSW Australia
School of Life Sciences, Faculty of Science, The University of Technology Sydney, Ultimo, NSW, Australia
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
Groningen Research Institute for Asthma and COPD University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
Groningen Research Institute for Asthma and COPD University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Pieter Sicco Hiemstra Aachen Department of Pulmonology Leiden University Medical Center Leiden The Netherlands Dept of Pulmonology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Pulmonology Leiden University Medical Center Leiden The Netherlands
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
OMNI‐Biomarker Development, Genentech Inc South San Francisco CA USA
OMNI-Biomarker Development, Genentech Inc, South San Francisco, CA, USA
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Affiliation as printed
OMNI‐Biomarker Development, Genentech Inc South San Francisco CA USA
OMNI-Biomarker Development, Genentech Inc, South San Francisco, CA, USA
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Affiliation as printed
OMNI‐Biomarker Development, Genentech Inc South San Francisco CA USA
OMNI-Biomarker Development, Genentech Inc, South San Francisco, CA, USA
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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University of Technology Sydney
Affiliation as printed
School of Life Sciences Faculty of Science The University of Technology Sydney Ultimo NSW Australia
School of Life Sciences, Faculty of Science, The University of Technology Sydney, Ultimo, NSW, Australia
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QIMR Berghofer Medical Research Institute
Affiliation as printed
QIMR Berghofer Medical Research Institute Herston Qld Australia
QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
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Affiliation as printed
Biomedicine Discovery Institute and Department of Pharmacology School of Biomedical Sciences Monash University Melbourne Vic. Australia
Biomedicine Discovery Institute and Department of Pharmacology, School of Biomedical Sciences, Monash University, Melbourne, Vic., Australia
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Maria B. Sukkar corresponding
University of Technology Sydney
Affiliation as printed
Graduate School of Health Faculty of Health The University of Technology Sydney Ultimo NSW Australia
Graduate School of Health, Faculty of Health, The University of Technology Sydney, Ultimo, NSW, Australia
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