Non-canonical inflammasome activation in Natural Killer cells: should all the focus be on macrophages and neutrophils?

The non-canonical inflammasome (NCI) is a crucial intracellular lipopolysaccharide (LPS) sensor and inflammatory activator in the host immune response to bacteria. This caspase-activating platform indirectly induces secretion of proinflammatory cytokines such as IL-1ꞵ and promotes a lytic form of cell death termed pyroptosis. The study of the NCI has mainly included the use of macrophages, neutrophils and epithelial cells which have all been reported to possess functional NCI activity. However, there are many lymphoid cell populations involved in the immune response to bacteria including invariant natural killer T cells (iNKTs), natural killer cells (NKs) and CD8+ T cells that so far have not been investigated for NCI activity. In this study, we utilised primary cells from mouse spleen and human blood to assess NCI activation in NK cells. In the context of intracellular bacterial infection NK cells can utilise their known cytotoxic and cytokine producing functions to resolve infection. Overactivation of this proinflammatory state in NK cells has been linked to increased sepsis disease severity. However, so far the NCI has not been implicated in these responses for NK cells. Our preliminary results presented in this thesis demonstrate that both mouse and human NK cells express inflammasome related genes at the transcriptional level but that only human NK cells are able to fully activate the NCI in response to intracellular LPS transfection through secretion of IL-1ꞵ. However, LPS transfection did not induce pyroptotic cell death in NK cells. Only with infection experiments using Salmonella Typhimurium could pyroptosis be induced. Further work is needed to unravel the cell specific mechanisms underpinning this phenotype. As such, our research indicates that lymphoid cell populations merit further investigation in the field of inflammasome biology.