Inflammasomes respond to infection or cellular stress to activate caspase-1 which leads to the maturation and secretion of interleukin 1 beta (IL-1β) and IL-18, and to pyroptotic cell death. NLRP3 is the best characterised inflammasome and has been shown to be activated by multiple pathogens and cellular insults in myeloid cells. A key substrate for caspase 1 is gasdermin D, whose cleavage leads to membrane pore formation to facilitate cytokine release and pyroptosis. However, the involvement of inflammasomes in RNA virus- and dsRNA-stimulated cytokine release and cell death are still being elucidated, especially with regard to epithelial cells which have a key role in early innate immune responses to respiratory viruses. In this study we demonstrate that the transfection of poly (I:C), a synthetic analog of double-stranded RNA (dsRNA), induces caspase-dependent but NLRP3-independent IL-1β and IL-18 secretion, and cell death in primary human bronchial epithelial cells. Using pharmacologic inhibition, we showed that unlike cytokine secretion, cell death is dependent on caspase-3, caspase-8 and caspase-9 but not on caspase-1. Interestingly dsRNA induces caspase-3/8/9-dependent gasdermin D inactivation but generates a gasdermin E pore forming fragment. Thus, dsRNA induces inflammasome-dependent cytokine secretion, and cell death, in human respiratory epithelial cells. Further cytokine secretion and cell death are mediated by multiple caspases and likely involve gasdermin E rather than gasdermin D pores. Finally this model is being tested for RNA viruses, in particular respiratory syncytial virus.

Innate immune recognition of dsRNA in respiratory epithelial cells induces IL-1 and IL-18 secretion, cell death and GSDME cleavage

Exploring the intricacies of host-pathogen communication is vital in order to understand why
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