Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes.
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Vigano E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A
Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes.
Nat Commun. 2015 Oct 28;6:8761. doi: 10.1038/ncomms9761.
- PubMed ID
- 26508369 [ View in PubMed]
- Abstract
Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1beta. The biologically inactive IL-1beta 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-1alpha and IL-1beta 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.