Dataset Information

AIM2 Inflammasome Activation Leads to IL-1? and TGF-? Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is now the fourth-leading cause of death worldwide and its prevalence is increasing. The progressive decline of lung function and airway remodelling are a consequence of chronic inflammatory responses. It was recently postulated the involvement of the inflammasome in COPD, although the underlying mechanism/s still need to be elucidated. Therefore, we isolated peripheral blood mononuclear cells (PBMCs) from exacerbated/unstable COPD patients. The stimulation of PBMCs with an AIM2 inflammasome activator, Poly dA:dT, led to IL-1?, but not IL-1?, release. The release of this cytokine was caspase-1- and caspase-4-dependent and correlated to higher levels of 8-OH-dG in COPD compared to non-smoker and smoker-derived PBMCs. Interestingly, AIM2-depedent IL-1? release was responsible for higher TGF-? levels, crucial mediator during pro-fibrotic processes associated to COPD progression. In conclusion, our data highlight the involvement of AIM2/caspase-1/caspase-4 in IL-1?-induced TGF-? release in unstable COPD-derived PBMCs, opening new therapeutic perspectives for unstable COPD patients.

SUBMITTER: Colarusso C

PROVIDER: S-EPMC6428726 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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AIM2 Inflammasome Activation Leads to IL-1α and TGF-β Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells.

Colarusso Chiara C Terlizzi Michela M Molino Antonio A Imitazione Pasquale P Somma Pasquale P Rega Roberto R Saccomanno Antonello A Aquino Rita P RP Pinto Aldo A Sorrentino Rosalinda R

Frontiers in pharmacology 20190315

Chronic obstructive pulmonary disease (COPD) is now the fourth-leading cause of death worldwide and its prevalence is increasing. The progressive decline of lung function and airway remodelling are a consequence of chronic inflammatory responses. It was recently postulated the involvement of the inflammasome in COPD, although the underlying mechanism/s still need to be elucidated. Therefore, we isolated peripheral blood mononuclear cells (PBMCs) from exacerbated/unstable COPD patients. The stimu ...[more]

PMID: 30930781

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Project description:Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by persistent respiratory symptoms and progressive airflow limitation as a consequence of a chronic inflammatory response. Corticosteroids are the main treatment for COPD patients with a history of exacerbation, in that they attenuate exacerbation and dyspnea, and improve the response to bronchodilators. Nevertheless, despite corticosteroid administration, COPD patients still undergo exacerbation phases. In this context, the aim of this study was to evaluate the activity of Absent in melanoma 2 (AIM2) inflammasome-dependent pathways under corticosteroid treatment during COPD exacerbation. Stable and exacerbated COPD-derived Peripheral Blood Mononuclear Cells (PBMCs) were treated with a well-known anti-inflammatory agent, Dexamethasone (DEX), in the presence or not of Poly (deoxyadenylic-deoxythymidylate) acid (Poly dA:dT), an AIM2 ligand. We found that IL-1? was highly increased when AIM2 was activated from Poly dA:dT in exacerbated, but not in stable, COPD-derived PBMCs. To note, the release of IL-1? after the stimulation of AIM2 in PBMCs obtained from stable (hospitalized) COPD patients was not higher from the basal conditions, though it was still as high as that observed for Poly dA:dT-stimulated PBMCs obtained from exacerbated patients. This effect was associated with a higher expression of AIM2 in pair-matched circulating CD14+ cells obtained from hospitalized patients who passed from the exacerbation to stable status. Because the difference between stable and exacerbated COPD patients relies on the treatment with corticosteroids, exacerbated and stable COPD-derived PBMCs were treated with DEX. Indeed, the release of IL-1? and TGF-? was not altered after DEX treatment. In conclusion, we found that the administration of DEX in vitro on exacerbated COPD-derived PBMCs was not able to revert the detrimental inflammatory mechanism associated with AIM2 activation responsible for the release of IL-1? and the ensuing TGF-?, contributing to the severity of disease.

Project description:AIM2, a cytosolic DNA sensor, plays an important role during infection caused by pathogens with double-stranded DNA; however, its role in human cytomegalovirus (HCMV) infection remains unclear. Previously, we showed an increase in AIM2 protein levels during the early stage of HCMV infection and a decrease 24 h post infection. Because HCMV has developed a variety of strategies to evade host immunity, we speculated that this decline might be attributed to a viral immune escape mechanism. The tegument protein pUL83 is an important immune evasion protein and several studies have reported that pUL83 binds to specific cellular proteins, such as AIM2-like receptor IFI16, to affect their functions. To determine whether pUL83 contributes to the variation in AIM2 levels during HCMV infection, we investigated the pUL83/AIM2 interaction and its impact on the AIM2 inflammasome activation.We constructed plasmids expressing recombinant pUL83 and AIM2 proteins for two-hybrid and chemiluminescence assays. Using co-immunoprecipitation and immunofluorescent co-localization, we confirmed the interaction of pUL83/AIM2 in THP-1-derived macrophages infected with HCMV AD169 strain. Furthermore, by investigating the expression and cleavage of inflammasome-associated proteins in recombinant HEK293T cells expressing AIM2, apoptosis-associated speck-like protein (ASC), pro-caspase-1 and pro-IL-1?, we evaluated the effect of pUL83 on the AIM2 inflammasome.An interaction between pUL83 and AIM2 was detected in macrophages infected with HCMV as well as in transfected HEK293T cells. Moreover, transfection of the pUL83 expression vector into recombinant HEK293T cells stimulated by poly(dA:dT) resulted in reduced expression and activation of AIM2 inflammasome-associated proteins, compared with the absence of pUL83.Our data indicate that pUL83 interacts with AIM2 in the cytoplasm during the early stages of HCMV infection. The pUL83/AIM2 interaction deregulates the activation of AIM2 inflammasome. These findings reveal a new strategy of immune evasion developed by HCMV, which may facilitate latent infection.

Dataset Information

AIM2 Inflammasome Activation Leads to IL-1? and TGF-? Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells.

Publications

AIM2 Inflammasome Activation Leads to IL-1α and TGF-β Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells.

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