RAGE and TLR4 differentially regulate airway hyperresponsiveness: implications for COPD.

Allam, VSRR; Faiz, A; Lam, M; Rathnayake, SNH; Ditz, B; Pouwels, SD; Brandsma, C-A; Timens, W; Hiemstra, PS; Tew, GW; Neighbors, M; Grimbaldeston, M; van den Berge, M; Donnelly, S; Phipps, S; Bourke, JE; Sukkar, MB

RAGE and TLR4 differentially regulate airway hyperresponsiveness: implications for COPD.

Allam, VSRR Faiz, A

Lam, M Rathnayake, SNH Ditz, B Pouwels, SD Brandsma, C-A Timens, W Hiemstra, PS Tew, GW Neighbors, M Grimbaldeston, M van den Berge, M Donnelly, S

Phipps, S Bourke, JE Sukkar, MB

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Publisher:: John Wiley and Sons
Publication Type:: Journal Article
Citation:: Allergy, 2021, 76, (4), pp. 1123-1135
Issue Date:: 2021-01-01

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Field	Value	Language
dc.contributor.author	Allam, VSRR
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Lam, M
dc.contributor.author	Rathnayake, SNH
dc.contributor.author	Ditz, B
dc.contributor.author	Pouwels, SD
dc.contributor.author	Brandsma, C-A
dc.contributor.author	Timens, W
dc.contributor.author	Hiemstra, PS
dc.contributor.author	Tew, GW
dc.contributor.author	Neighbors, M
dc.contributor.author	Grimbaldeston, M
dc.contributor.author	van den Berge, M
dc.contributor.author	Donnelly, S https://orcid.org/0000-0003-2005-3698
dc.contributor.author	Phipps, S
dc.contributor.author	Bourke, JE
dc.contributor.author	Sukkar, MB
dc.date.accessioned	2021-12-06T03:19:30Z
dc.date.available	2020-07-14
dc.date.available	2021-12-06T03:19:30Z
dc.date.issued	2021-01-01
dc.identifier.citation	Allergy, 2021, 76, (4), pp. 1123-1135
dc.identifier.issn	0105-4538
dc.identifier.issn	1398-9995
dc.identifier.uri	http://hdl.handle.net/10453/152138
dc.description.abstract	BACKGROUND:The receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) are implicated in COPD. Although these receptors share common ligands and signaling 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 hyperreactivity (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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	John Wiley and Sons
dc.relation.ispartof	Allergy
dc.relation.isbasedon	10.1111/all.14563
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1107 Immunology
dc.subject.classification	Allergy
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Respiratory Hypersensitivity
dc.subject.mesh	Mitogen-Activated Protein Kinases
dc.subject.mesh	Antigens, Neoplasm
dc.subject.mesh	Smoking
dc.subject.mesh	Toll-Like Receptor 4
dc.subject.mesh	Receptor for Advanced Glycation End Products
dc.subject.mesh	Animals
dc.subject.mesh	Antigens, Neoplasm
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mitogen-Activated Protein Kinases
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Receptor for Advanced Glycation End Products
dc.subject.mesh	Respiratory Hypersensitivity
dc.subject.mesh	Smoking
dc.subject.mesh	Toll-Like Receptor 4
dc.title	RAGE and TLR4 differentially regulate airway hyperresponsiveness: implications for COPD.
dc.type	Journal Article
utslib.citation.volume	76
utslib.location.activity	Denmark
utslib.for	1107 Immunology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Students
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
pubs.consider-herdc	true
dc.date.updated	2021-12-06T03:19:28Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	76
utslib.citation.issue	4

Abstract:

BACKGROUND:The receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) are implicated in COPD. Although these receptors share common ligands and signaling 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 hyperreactivity (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.

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http://hdl.handle.net/10453/152138