Role of the Inflammasome-Caspase1/11-IL-1/18 Axis in Cigarette Smoke Driven Airway Inflammation: An Insight into the Pathogenesis of COPD

Abstract

BackgroundChronic Obstructive Pulmonary Disease (COPD) is an inflammatory airway disease often associated with cigarette smoke (CS) exposure. The disease is increasing in global prevalence and there is no effective therapy. A major step forward would be to understand the disease pathogenesis. The ATP-P2X7 pathway plays a dominant role in murine models of CS induced airway inflammation, and markers of activation of this axis are upregulated in patients with COPD. This strongly suggests that the axis could be important in the pathogenesis of COPD. The aim of this study was to perform a detailed characterisation of the signalling pathway components involved in the CS-driven, P2X7 dependent airway inflammation.MethodsWe used a murine model system, bioassays and a range of genetically modified mice to better understand this complex signalling pathway.ResultsThe inflammasome-associated proteins NALP3 and ASC, but not IPAF and AIM2, are required for CS-induced IL-1β/IL-18 release, but not IL-1α. This was associated with a partial decrease in lung tissue caspase 1 activity and BALF neutrophilia. Mice missing caspase 1/11 or caspase 11 had markedly attenuated levels of all three cytokines and neutrophilia. Finally the mechanism by which these inflammatory proteins are involved in the CS-induced neutrophilia appeared to be via the induction of proteins involved in neutrophil transmigration e.g. E-Selectin.ConclusionThis data indicates a key role for the P2X7-NALP3/ASC-caspase1/11-IL-1β/IL-18 axis in CS induced airway inflammation, highlighting this pathway as a possible therapeutic target for the treatment of COPD.

Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD)

“…Increases in ATP levels have been reported in in vitro/in vivo models of COPD [65,66] and in clinical samples [67,68]. This increase in ATP levels has been suggested to play a role in the chemotaxis and activation of inflammatory cells, such as neutrophils, through P2Y and P2X7 receptors [62][63][64]. Eltom et al [61] demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL1b/IL-18) in the lungs.…”

“…Recently it has been shown that levels of an activator of the NLRP3 inflammasome, ATP, are increased in pre-clinical smoke-exposure models [61][62][63][64]. Increases in ATP levels have been reported in in vitro/in vivo models of COPD [65,66] and in clinical samples [67,68].…”

“…A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were nonfunctional attenuated caspase 1 activation, IL-1b release and airway neutrophilia. In an attempt to further explore the role of the P2X7 receptor in COPD inflammation Eltom et al [64] exposed mice to CS twice a day to induce COPD-like inflammation. They demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation (increased caspase 1 activity and release of IL-1b/IL-18) in the lungs.…”

Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease

“…Evidence for NLRP3 involvement in acute inflammation associated with CS exposure has been further studied in mouse models (39)(40). Nlrp3 2/2 mice displayed reduced caspase-1 activation, IL-18/IL-1b production, and neutrophil influx in the bronchoalveolar lavage (BAL) relative to wild-type mice after acute CS exposure (39).…”

“…Nlrp3 2/2 mice displayed reduced caspase-1 activation, IL-18/IL-1b production, and neutrophil influx in the bronchoalveolar lavage (BAL) relative to wild-type mice after acute CS exposure (39). Genetic deletion of the P2X7 receptor also reduced CS-induced caspase-1 activation, IL-1b release, and airway neutrophilia during acute CS exposure (40).…”