GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1? Release under Caspase-1 Inhibition.

ABSTRACT: Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1? release, a key feature of pyroptosis, is absent, whereas IL-1? release is induced. Notably, unprocessed pro-IL-1? forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1? release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1? from dying cells.

SUBMITTER: Aizawa E 

PROVIDER: S-EPMC7200307 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature