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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.

Author information

1
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore. 8A Biomedical Grove, #04-06 Immunos, Singapore 138648, Singapore.
2
University of Milano-Bicocca, PhD program in Translational and Molecular Medicine (DIMET), Ospedale San Gerardo, Via Pergolesi 33, Monza (MB) 20900, Italy.
3
Faculty of Life Sciences, The University of Manchester, Carys Bannister Building, Dover Street, Manchester M13 9PT, UK.

Abstract

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.

PMID:
26508369
PMCID:
PMC4640152
DOI:
10.1038/ncomms9761
[Indexed for MEDLINE]
Free PMC Article

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