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.

Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pluripotent stem cell (hiPSC)-derived neuronal culture model that allows axonal VZV infection of the neurons, thereby mimicking the natural route of infection. Using this model, we showed that hiPSC-neurons do not mount an effective interferon-mediated antiviral response following VZV infection. Indeed, in contrast to infection with Sendai virus, VZV infection of the hiPSC-neurons does not result in the upregulation of interferon-stimulated genes (ISGs) that have direct antiviral functions. Furthermore, the hiPSC-neurons do not produce interferon-α (IFNα), a major cytokine that is involved in the innate antiviral response, even upon its stimulation with strong synthetic inducers. In contrast, we showed that exogenous IFNα effectively limits VZV spread in the neuronal cell body compartment and demonstrated that ISGs are efficiently upregulated in these VZV-infected neuronal cultures that are treated with IFNα. Thus, whereas the cultured hiPSC neurons seem to be poor IFNα producers, they are good IFNα responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFNα for VZV infection control.

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