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

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Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes
Title:
Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes
Other Titles:
Nature Communications
Keywords:
Publication Date:
28 October 2015
Citation:
Nature Communications 6, Article number: 8761 (2015)
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 Ca2+ 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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
Description:
ISSN:
2041-1723
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