Dataset Information

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

ABSTRACT: Inflammasomes activate the protease caspase-1, which cleaves interleukin-1? 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-1^C284A, 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-1^C284A, 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.

SUBMITTER: Schneider KS

PROVIDER: S-EPMC5750195 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Schneider Katharina S KS Groß Christina J CJ Dreier Roland F RF Saller Benedikt S BS Mishra Ritu R Gorka Oliver O Heilig Rosalie R Meunier Etienne E Dick Mathias S MS Ćiković Tamara T Sodenkamp Jan J Médard Guillaume G Naumann Ronald R Ruland Jürgen J Kuster Bernhard B Broz Petr P Groß Olaf O

Cell reports 20171201 13

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-1<sup>C284A</sup>, 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 activate ...[more]

PMID: 29281832

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Project description:Only a few types of inflammasomes have been described in central nervous system cells. Among these, the absent in melanoma 2 (AIM2) inflammasome is primarily found in neurons, is highly specific and can be activated only by double-stranded DNA. Although it has been demonstrated that the AIM2 inflammasome is activated by poly(deoxyadenylic-deoxythymidylic) acid sodium salt and leads to pyroptotic neuronal cell death, the role of AIM2 inflammasome-mediated pyroptosis in early brain injury (EBI) after subarachnoid haemorrhage (SAH) has rarely been studied. Thus, we designed this study to explore the mechanism of gasdermin D(GSDMD)-induced pyroptosis mediated by the AIM2 inflammasome in EBI after SAH. The level of AIM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The pathway of AIM2 inflammasome-mediated pyroptosis, the AIM2/Caspase-1/GSDMD pathway, was explored after experimental SAH in vivo and in primary cortical neurons stimulated by oxyhaemoglobin (oxyHb) in vitro. Then, we evaluated GSDMD-induced pyroptosis mediated by the AIM2 inflammasome in AIM2 and caspase-1- deficient mice and primary cortical neurons generated through lentivirus (LV) knockdown. Compared with that of the control samples, the AIM2 level in the CSF of the patients with SAH was significantly increased. Pyroptosis-associated proteins mediated by the AIM2 inflammasome were significantly increased in vivo and in vitro following experimentally induced SAH. After AIM2 and caspase-1 were knocked down by an LV, GSDMD-induced pyroptosis mediated by the AIM2 inflammasome was alleviated in EBI after SAH. Intriguingly, when caspase-1 was knocked down, apoptosis was significantly suppressed via impeding the activation of caspase-3. GSDMD-induced pyroptosis mediated by the AIM2 inflammasome may be involved in EBI following SAH. The inhibition of AIM2 inflammasome activation caused by knocking down AIM2 and caspase-1 alleviates GSDMD-induced pyroptosis in EBI after SAH.

Dataset Information

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

Publications

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

Similar Datasets

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