Abstract
NLRP-3 inflammasome activation can result in interleukin-1β (IL-1β) 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 β 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.
Highlights
To respond to pathogens and endogenous danger signals, cells of the innate immune system are endowed with the NLRP3 inflammasome
Monocytic caspase-1 activity was higher in blood pressure (BP) than haemodialysis patients (HD) patients, a result that does not apply to granulocytes and lymphocytes (Figure 1, left part)
Regarding the caspase-1 positivity of granulocytes and lymphocytes, it is clear that Casp-1++ cells are elevated in HD compared to BP (% granulocytes: 6.4 ± 5.9 vs. 3.4 ± 3.4, p = 0.054; % lymphocytes: 2.9 ± 2.7 vs. 1.2 ± 0.7, p = 0.011; Figure 1g) and prone to higher pyroptosis (% granulocytes: 35.8 ± 16.2 vs. 22.5 ± 14.2, p = 0.008; % lymphocytes: 32.9 ± 12.8 vs. 21.1 ± 16.5, p = 0.001; Figure 1h)
Summary
To respond to pathogens and endogenous danger signals, cells of the innate immune system are endowed with the NLRP3 inflammasome. The formation of the active NLRP3 protein complex leads to caspase-1 activation, which in turn can result in cleavage of pro-IL-1β and of gasdermin D. Active gasdermin D aggregates and forms pores in the cell membrane. The consequence of this is cell swelling and cell death, a process that is called pyroptosis. Mature IL-1β can leave the cell via gasdermin-formed pores or after the complete lysis of cells. The eminent importance of IL-1β is supported by the fact that there are still other ways, i.e., microvesicles, lysosomes and exosomes, by which
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