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

Abstract

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-β 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-β, contributing to the severity of disease.

AIM2 Nuclear Exit and Inflammasome Activation in Chronic Obstructive Pulmonary Disease and Response to Cigarette Smoke 

“…The discrepancies between our and other studies could be caused by either (i) varying degrees of COPD severity, and/or (ii) the cell types available for analysis, and/or (iii) the methods used for the detection of in ammasome activation. First, our data reveals a positive correlation between readouts of the airway AIM2 in ammasome activation and GOLD stages, which is in line with recent data indicating AIM2 in ammasome activation in peripheral blood during exacerbation ares [14,15]. Second, although in this study in ammasome activation was shown not to be limited to the myeloid lineage, with epithelial cells clearly showing cleavage of IL-1β and cytoplasmic AIM2 specks correlated with GOLD stages, numbers of 'positive' epithelial cells remained an order lower than in alveolar macrophages.…”

“…Recent studies reported AIM2 in ammasome pathway upregulation in peripheral blood mononuclear cells (PBMCs) of COPD patients during exacerbations but not during stable periods [14,15]. Although CD14+ PBMCs showed increased AIM2 protein expression in COPD patients compared to non-COPD smokers and healthy subjects [14], stimulation of PBMCs with poly-dA:dT as surrogate dsDNA was able to induce IL-1α release only when cells were obtained from exacerbated but not stable COPD patients [15]. The AIM2 in ammasome activation in this model triggered production of detrimental TGF-β [14] and could not be alleviated with dexamethasone [15].…”

“…The AIM2 in ammasome is activated by the inappropriate presence of double-stranded DNA (dsDNA) in the cytosolic compartment due to transport by pathogens, or leakage from damaged organelles [6]. Most in ammasome studies in COPD patients and cigarette smoke exposure models have focused on NLRP3 [9][10][11][12][13] but recent studies suggest involvement of the AIM2 in ammasome [14,15].…”

DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

“…In this review, the understanding of the DROSHA-miRNA-AIM2 inflammasome axis in the pathogenesis of IPF could be helpful to further investigate the field of interaction between the miRNA and AIM2 inflammasome during IPF. The evidence for the importance of AIM2 inflammasome activation in IPF and other lung diseases could provide the necessity of developing therapeutic agents for the AIM2 inflammasome [129][130][131]. Recent reports imply that the activation of the AIM2 inflammasome or other inflammasomes is a critical event during the severity of asthma and chronic obstructive pulmonary disease (COPD) [129][130][131].…”

“…The evidence for the importance of AIM2 inflammasome activation in IPF and other lung diseases could provide the necessity of developing therapeutic agents for the AIM2 inflammasome [129][130][131]. Recent reports imply that the activation of the AIM2 inflammasome or other inflammasomes is a critical event during the severity of asthma and chronic obstructive pulmonary disease (COPD) [129][130][131]. A new study, which could discover a therapeutic approach to the control of inflammasomes in various lung diseases, is needed.…”