Journal
NATURE IMMUNOLOGY
Volume 20, Issue 3, Pages 276-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-018-0303-z
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Categories
Funding
- [CA180779]
- [CA200422]
- [AI073099]
- [AI116585]
- [AI129496]
- [AI140718]
- [AI140705]
- [DE023926]
- [DE027888]
- [DE028521]
- [NRF-2016R1D1A1B03931761]
- [Al124491]
- [HD087988]
- [AI081719]
- [AI117211]
- [AI127954]
- [AI106375]
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Inflammatory caspases (caspase-1, caspase-4, caspase-5 and caspase-11 (caspase-1/-4/-5/-11)) mediate host defense against microbial infections, processing pro-inflammatory cytokines and triggering pyroptosis. However, precise checkpoints are required to prevent their unsolicited activation. Here we report that serpin family B member 1 (SERPINB1) limited the activity of those caspases by suppressing their caspase-recruitment domain (CARD) oligomerization and enzymatic activation. While the reactive center loop of SERPINB1 inhibits neutrophil serine proteases, its carboxy-terminal CARD-binding motif restrained the activation of pro-caspase-1/-4/-5/-11. Consequently, knockdown or deletion of SERPINB1 prompted spontaneous activation of caspase-1/-4/-5/-11, release of the cytokine IL-1 beta and pyroptosis, inducing elevated inflammation after non-hygienic co-housing with pet-store mice and enhanced sensitivity to lipopolysaccharide- or Acinetobacter baumannii-induced endotoxemia. Our results reveal that SERPINB1 acts as a vital gatekeeper of inflammation by restraining neutrophil serine proteases and inflammatory caspases in a genetically and functionally separable manner.
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