The nucleotide-binding domain and leucine-rich repeat protein-3 inflammasome is not activated in airway smooth muscle upon toll-like receptor-2 ligation

Hirota, JA; Im, H; Rahman, MM; Rumzhum, NN; Manetsch, M; Pascoe, CD; Bunge, K; Alkhouri, H; Oliver, BG; Ammit, AJ

The nucleotide-binding domain and leucine-rich repeat protein-3 inflammasome is not activated in airway smooth muscle upon toll-like receptor-2 ligation

Hirota, JA Im, H Rahman, MM Rumzhum, NN Manetsch, M Pascoe, CD Bunge, K Alkhouri, H Oliver, BG

Ammit, AJ

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Publication Type:: Journal Article
Citation:: American Journal of Respiratory Cell and Molecular Biology, 2013, 49 (4), pp. 517 - 524
Issue Date:: 2013-10-01

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Field	Value	Language
dc.contributor.author	Hirota, JA	en_US
dc.contributor.author	Im, H	en_US
dc.contributor.author	Rahman, MM	en_US
dc.contributor.author	Rumzhum, NN	en_US
dc.contributor.author	Manetsch, M	en_US
dc.contributor.author	Pascoe, CD	en_US
dc.contributor.author	Bunge, K	en_US
dc.contributor.author	Alkhouri, H	en_US
dc.contributor.author	Oliver, BG https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.issued	2013-10-01	en_US
dc.identifier.citation	American Journal of Respiratory Cell and Molecular Biology, 2013, 49 (4), pp. 517 - 524	en_US
dc.identifier.issn	1044-1549	en_US
dc.identifier.uri	http://hdl.handle.net/10453/28523
dc.description.abstract	Inflammasomes have emerged as playing key roles in inflammation and innate immunity. A growing body of evidence has suggested that the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasomeisimportant inchronic airwaydiseases suchas asthma and chronic obstructive pulmonary disease. Inflammasome activation results, in part, in pro-IL-1β processing and the secretion of the proinflammatory cytokine IL-1β. Because asthma exacerbations are associated with elevated concentrations of secreted IL-1β, we addressed whether the NLRP3 inflammasome is activated under in vitro conditions that mimic infectious exacerbations in asthma. Primary cultures of airway smoothmuscle (ASM) cells were treated with infectious stimuli (mimicked using the Toll-like receptor-2 agonist Pam3CSK4, a synthetic bacterial lipopeptide).Whereas Pam3CSK4 robustlyup-regulatedASMcytokineexpressionin response toTNF-αand significantly enhanced IL-1β mRNA expression, we were unable to detect IL-1β in the cell supernatants. Thus, IL-1β was not secreted and therefore was unable to act in an autocrine manner to promote the amplification of ASMinflammatory responses.Moreover, Toll-like receptor-2 ligation did not enhanceNLRP3 or caspase-1 expression in ASM cells, and NLRP3 and caspase-1 protein were not present in the ASM layer of tracheal sections from human donors. In conclusion, these data demonstrate that the enhanced synthetic function of ASM cells, induced by infectious exacerbations of airway inflammation, is NLRP3 inflammasome-independent and IL-1β-independent. Activation of the NLRP3 inflammasome by invading pathogens may prove cell type-specific in exacerbations of airway inflammation in asthma. Copyright © 2013 by the American Thoracic Society.	en_US
dc.relation.ispartof	American Journal of Respiratory Cell and Molecular Biology	en_US
dc.relation.isbasedon	10.1165/rcmb.2013-0047OC	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Muscle, Smooth	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Myocytes, Smooth Muscle	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Inflammation	en_US
dc.subject.mesh	Caspase 1	en_US
dc.subject.mesh	Nucleotides	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Carrier Proteins	en_US
dc.subject.mesh	Protein Structure, Tertiary	en_US
dc.subject.mesh	Protein Binding	en_US
dc.subject.mesh	Toll-Like Receptor 2	en_US
dc.subject.mesh	Interleukin-1beta	en_US
dc.subject.mesh	Lipopeptides	en_US
dc.subject.mesh	Inflammasomes	en_US
dc.subject.mesh	NLR Family, Pyrin Domain-Containing 3 Protein	en_US
dc.title	The nucleotide-binding domain and leucine-rich repeat protein-3 inflammasome is not activated in airway smooth muscle upon toll-like receptor-2 ligation	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	49	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	49	en_US

Abstract:

Inflammasomes have emerged as playing key roles in inflammation and innate immunity. A growing body of evidence has suggested that the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasomeisimportant inchronic airwaydiseases suchas asthma and chronic obstructive pulmonary disease. Inflammasome activation results, in part, in pro-IL-1β processing and the secretion of the proinflammatory cytokine IL-1β. Because asthma exacerbations are associated with elevated concentrations of secreted IL-1β, we addressed whether the NLRP3 inflammasome is activated under in vitro conditions that mimic infectious exacerbations in asthma. Primary cultures of airway smoothmuscle (ASM) cells were treated with infectious stimuli (mimicked using the Toll-like receptor-2 agonist Pam3CSK4, a synthetic bacterial lipopeptide).Whereas Pam3CSK4 robustlyup-regulatedASMcytokineexpressionin response toTNF-αand significantly enhanced IL-1β mRNA expression, we were unable to detect IL-1β in the cell supernatants. Thus, IL-1β was not secreted and therefore was unable to act in an autocrine manner to promote the amplification of ASMinflammatory responses.Moreover, Toll-like receptor-2 ligation did not enhanceNLRP3 or caspase-1 expression in ASM cells, and NLRP3 and caspase-1 protein were not present in the ASM layer of tracheal sections from human donors. In conclusion, these data demonstrate that the enhanced synthetic function of ASM cells, induced by infectious exacerbations of airway inflammation, is NLRP3 inflammasome-independent and IL-1β-independent. Activation of the NLRP3 inflammasome by invading pathogens may prove cell type-specific in exacerbations of airway inflammation in asthma. Copyright © 2013 by the American Thoracic Society.

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http://hdl.handle.net/10453/28523