Activation of the absent in melanoma 2 inflammasome in peripheral blood mononuclear cells from Idiopathic pulmonary fibrosis patients leads to the release of pro-fibrotic mediators

Terlizzi, M; Molino, A; Colarusso, C; Donovan, C; Imitazione, P; Somma, P; Aquino, RP; Hansbro, PM; Pinto, A; Sorrentino, R

Activation of the absent in melanoma 2 inflammasome in peripheral blood mononuclear cells from Idiopathic pulmonary fibrosis patients leads to the release of pro-fibrotic mediators

Terlizzi, M Molino, A Colarusso, C Donovan, C Imitazione, P Somma, P Aquino, RP Hansbro, PM

Pinto, A Sorrentino, R

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Publication Type:: Journal Article
Citation:: Frontiers in Immunology, 2018, 9 (APR)
Issue Date:: 2018-04-05

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Field	Value	Language
dc.contributor.author	Terlizzi, M	en_US
dc.contributor.author	Molino, A	en_US
dc.contributor.author	Colarusso, C	en_US
dc.contributor.author	Donovan, C	en_US
dc.contributor.author	Imitazione, P	en_US
dc.contributor.author	Somma, P	en_US
dc.contributor.author	Aquino, RP	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Pinto, A	en_US
dc.contributor.author	Sorrentino, R	en_US
dc.date.available	2018-03-19	en_US
dc.date.issued	2018-04-05	en_US
dc.identifier.citation	Frontiers in Immunology, 2018, 9 (APR)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128231
dc.description.abstract	© 2018 Terlizzi, Molino, Colarusso, Donovan, Imitazione, Somma, Aquino, Hansbro, Pinto and Sorrentino. Idiopathic pulmonary fibrosis (IPF) is a chronic fibro-proliferative disease characterized by poor prognosis, with a mean survival of ~2-3 years after definite diagnosis. The cause of IPF is still unknown but it is a heterogeneous condition in which the aberrant deposition of extracellular matrix leads to extensive lung remodeling. This remodeling is a consequence of inflammatory responses, but the mechanisms involved are poorly understood. In this study, we first analyzed a bleomycin-induced mouse model, which showed that higher expression of IL-1β, but not IL-18, was correlated to pulmonary cell infiltration and fibrosis. Then, we found that peripheral blood mononuclear cells (PBMCs) from IPF patients released IL-1α and IL-18 in a NLRP3- and calpain-independent manner after LPS ± ATP stimulation. Instead, the activation of the absent in melanoma 2 (AIM2) inflammasome induced the release of IL-1α in a caspase-1-/caspase-8-independent manner; whereas IL-18 release was caspase-1 dependent. These effects correlated with the release of the pro-fibrotic TGF-β, which was induced by AIM2 activation in a caspase-1- and TLR4-independent manner, but dependent on IL-1α. In this context, the activation of AIM2 induced the release of caspase-4 from IPF-derived PBMCs, which correlated with the mRNA levels of this caspase that was higher in IPF than in healthy PBMCs. In conclusion, our findings identify a novel molecular mechanism whereby the activation of AIM2 could lead to the activation of the non-canonical inflammasome (caspase-4 dependent) that induces the release of IL-1α responsible for the release of TGF-β from PBMCs of IPF patients.	en_US
dc.relation.ispartof	Frontiers in Immunology	en_US
dc.relation.isbasedon	10.3389/fimmu.2018.00670	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Bleomycin	en_US
dc.subject.mesh	Caspases, Initiator	en_US
dc.subject.mesh	Cytokines	en_US
dc.subject.mesh	DNA-Binding Proteins	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Idiopathic Pulmonary Fibrosis	en_US
dc.subject.mesh	Inflammasomes	en_US
dc.subject.mesh	Leukocytes, Mononuclear	en_US
dc.subject.mesh	Mice, Inbred BALB C	en_US
dc.subject.mesh	Middle Aged	en_US
dc.title	Activation of the absent in melanoma 2 inflammasome in peripheral blood mononuclear cells from Idiopathic pulmonary fibrosis patients leads to the release of pro-fibrotic mediators	en_US
dc.type	Journal Article
utslib.citation.volume	APR	en_US
utslib.citation.volume	9	en_US
utslib.for	1107 Immunology	en_US
utslib.for	1108 Medical Microbiology	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
utslib.copyright.status	open_access
pubs.issue	APR	en_US
pubs.publication-status	Published	en_US
pubs.volume	9	en_US

Abstract:

© 2018 Terlizzi, Molino, Colarusso, Donovan, Imitazione, Somma, Aquino, Hansbro, Pinto and Sorrentino. Idiopathic pulmonary fibrosis (IPF) is a chronic fibro-proliferative disease characterized by poor prognosis, with a mean survival of ~2-3 years after definite diagnosis. The cause of IPF is still unknown but it is a heterogeneous condition in which the aberrant deposition of extracellular matrix leads to extensive lung remodeling. This remodeling is a consequence of inflammatory responses, but the mechanisms involved are poorly understood. In this study, we first analyzed a bleomycin-induced mouse model, which showed that higher expression of IL-1β, but not IL-18, was correlated to pulmonary cell infiltration and fibrosis. Then, we found that peripheral blood mononuclear cells (PBMCs) from IPF patients released IL-1α and IL-18 in a NLRP3- and calpain-independent manner after LPS ± ATP stimulation. Instead, the activation of the absent in melanoma 2 (AIM2) inflammasome induced the release of IL-1α in a caspase-1-/caspase-8-independent manner; whereas IL-18 release was caspase-1 dependent. These effects correlated with the release of the pro-fibrotic TGF-β, which was induced by AIM2 activation in a caspase-1- and TLR4-independent manner, but dependent on IL-1α. In this context, the activation of AIM2 induced the release of caspase-4 from IPF-derived PBMCs, which correlated with the mRNA levels of this caspase that was higher in IPF than in healthy PBMCs. In conclusion, our findings identify a novel molecular mechanism whereby the activation of AIM2 could lead to the activation of the non-canonical inflammasome (caspase-4 dependent) that induces the release of IL-1α responsible for the release of TGF-β from PBMCs of IPF patients.

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http://hdl.handle.net/10453/128231