TY - JOUR
T1 - Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes
AU - Viganò, Elena
AU - Diamond, Catherine Emma
AU - Spreafico, Roberto
AU - Balachander, Akhila
AU - Sobota, Radoslaw M.
AU - Mortellaro, Alessandra
N1 - Funding Information:
We are grateful to the anonymous donors who provided blood samples and to the National University Hospital Blood Bank (Singapore) for help and support. We thank past and present lab members for their assistance and constructive comments. We also thank Gennaro De Libero, Maria Curotto de Lafaille, Lucia Mori and Neil McCarthy for critical review and editing of the manuscript. This research was funded by a SIgN core grant (A*STAR, Singapore).
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/10/28
Y1 - 2015/10/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84945542875&partnerID=8YFLogxK
U2 - 10.1038/ncomms9761
DO - 10.1038/ncomms9761
M3 - Article
C2 - 26508369
AN - SCOPUS:84945542875
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 8761
ER -