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Eur J Immunol. 2015 Oct;45(10):2911-7. doi: 10.1002/eji.201545523. Epub 2015 Aug 6.

Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells.

Author information

1
Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
2
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.

Abstract

Inflammasome activation culminates in activation of caspase-1, which leads to the maturation and subsequent release of cytokines of the interleukin 1 (IL-1) family and results in a particular form of cell death known as pyroptosis. In addition, in the murine system, a so-called non-canonical inflammasome involving caspase-11 has been described that directly responds to cytosolic LPS. Here, we show that the human monocytic cell line THP1 activates the inflammasome in response to cytosolic LPS in a TLR4-independent fashion. This response is mediated by caspase-4 and accompanied by caspase-1 activation, pyroptosis, and IL-1β maturation. In addition to caspase-4, efficient IL-1β conversion upon intracellular LPS delivery relies on potassium efflux, NLRP3, ASC, and caspase-1, indicating that although caspase-4 activation alone is sufficient to induce pyroptosis, this process depends on the NLRP3 inflammasome activation to drive IL-1β maturation. Altogether, this study provides evidence for the presence of a non-canonical inflammasome in humans and its dependence on caspase-4.

KEYWORDS:

Caspase-4; Myeloid cells; NLRP3; Non-canonical inflammasome

PMID:
26174085
DOI:
10.1002/eji.201545523
[Indexed for MEDLINE]
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