Cell Reports
Volume 21, Issue 13, 26 December 2017, Pages 3846-3859
Journal home page for Cell Reports

Article
The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity

https://doi.org/10.1016/j.celrep.2017.12.018Get rights and content
Under a Creative Commons license
open access

Highlights

  • Interplay of caspase-1 and caspase-8 revealed by analysis of Caspase1C284A mice

  • GSDMD-dependent pyroptosis suppresses caspase-8 activation at the inflammasome

  • The inflammasome engages caspase-8-driven secondary pyroptosis and IL-1 release

  • GSDMD-independent mechanisms contribute to inflammasome-mediated host protection

Summary

Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.

Keywords

caspase-1
IL-1
caspase-8
inflammasome
ASC
pyroptosis
regulated necrosis
gasdermin

Cited by (0)

12

Lead Contact