Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adapter ASC and assembly of an ASC speck. ASC specks recruit and activate caspase-1, which induces IL-1β cytokine maturation and pyroptotic cell death. Here we show that after pyroptosis ASC specks accumulate in the extracellular space, where they promote further IL-1β maturation. In addition, phagocytosis of ASC specks induces lysosomal damage, nucleation of soluble ASC as well as caspase-1 and IL-1β activation in the recipient cell. ASC specks appear in bodily fluids from inflamed tissues and autoantibodies against ASC specks develop in patients and animals with autoimmune pathologies. Together, these findings reveal extracellular functions of ASC specks and a novel form of cell-to-cell communication.

26Background: Severe, steroid-insensitive asthma is a substantial clinical problem accounting 27

COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.

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At a GlanceScientific Knowledge on the Subject Emphysema and COPD are likely underpinned by aberrant cell death that leads to airway inflammation and remodelling and emphysema. Apoptotic cell death can be programmed and controlled during apoptosis, whereas necroptosis defined by ruptured cell membranes is considered to be non-inflammatory, whereas necroptosis, a form of regulated necrosis, is highly pro-inflammatory. The roles of these pathways in COPD are poorly understood. What the Study Adds to the FieldWe used combination analysis of human COPD lung tissue, mouse models of experimental COPD, mice deficient in key necroptotic pathway mediators (RIPK3, MLKL) and inhibitors to define the roles of cell death pathways. Necroptotsis signalling is increased in the lungs in human and experimental COPD and correlate with disease severity. Genetic inhibition of necroptosis suppresses airway inflammation and remodelling and emphysema in experimental COPD, while pharmacological caspase inhibition reduces inflammation only.Inhibiting necroptosis may be a new therapeutic approach for COPD.