AIM2/IL-1α/TGF-ß Axis in PBMCs From Exacerbated Chronic Obstructive Pulmonary Disease (COPD) Patients Is Not Related to COX-2-Dependent Inflammatory Pathway.

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-1α 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-1α 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-1α and TGF-ß 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-1α and the ensuing TGF-ß, contributing to the severity of disease.

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

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-1α, but not IL-1ß, 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-1α release was responsible for higher TGF-ß 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-1α-induced TGF-ß release in unstable COPD-derived PBMCs, opening new therapeutic perspectives for unstable COPD patients.