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Nat Commun. 2015 Oct 28;6:8761. doi: 10.1038/ncomms9761.

Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes.

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Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore. 8A Biomedical Grove, #04-06 Immunos, Singapore 138648, Singapore.
University of Milano-Bicocca, PhD program in Translational and Molecular Medicine (DIMET), Ospedale San Gerardo, Via Pergolesi 33, Monza (MB) 20900, Italy.
Faculty of Life Sciences, The University of Manchester, Carys Bannister Building, Dover Street, Manchester M13 9PT, UK.


Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1β. The biologically inactive IL-1β precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown. Here we report that caspase-4 and caspase-5 mediate IL-1α and IL-1β release from human monocytes after LPS stimulation. Although caspase-4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment. We also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion. This one-step pathway requires Syk activity and Ca(2+) flux instigated by CD14/TLR4-mediated LPS internalization. Identification of caspase-4/5 as the key determinants of one-step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock.

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