Pyroptosis: A Common Feature of Immune Cells of Haemodialysis Patients

NLRP-3 inflammasome activation can result in interleukin-1 beta (IL-1 beta) release and inflammatory cell death (pyroptosis). Caspase-1 is able to trigger both processes. However, other caspases, caspase-4, -5 and -8, are believed to initiate pyroptosis without affecting IL-1 secretion. In this study, we evaluated two cardiovascular risk groups, haemodialysis patients (HD) and patients with intact kidney function but high blood pressure (BP), to analyse the mechanisms driving pyroptosis. Twenty HD were age-, gender- and diabetes-matched to BP. We found a common pyroptotic pattern in both patient groups, at which pyroptosis rates but not IL-1 beta levels were significantly higher in monocytes (HD vs. BP: p < 0.05), granulocytes (p < 0.01) and lymphocytes (p < 0.01) of HD patients. As uremic toxins are drivers of inflammation and regulated cell death, we applied a monocyte- and macrophage-like THP-1 model system to demonstrate that the protein-bound uremic toxin indoxyl sulfate (IS) is an inducer of pyroptotic cell death, particularly engaging caspase-4/caspase-5 and to a lesser extent caspase-8 and caspase-1. These data suggest that the uremic toxin IS can mediate pyroptosis in HD patients and the inflammatory caspase-4 and/or caspase-5 contribute to pyroptosis rates to a higher extent in comparison to caspase-1.

Automated summary

NLRP-3 inflammasome activation can lead to IL-1 beta release and pyroptosis. In this study, pyroptosis rates were significantly higher in HD patients compared to BP patients, without a significant difference in IL-1 beta levels. Uremic toxin IS may mediate pyroptosis in HD patients, with caspase-4 and/or caspase-5 playing a larger role compared to caspase-1.