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Eur J Immunol. 2015 Oct;45(10):2927-36. doi: 10.1002/eji.201545772. Epub 2015 Aug 6.

Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux.

Author information

1
Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

Abstract

Recognition of microbe-associated molecular patterns or endogenous danger signals by a subset of cytosolic PRRs results in the assembly of multiprotein signaling complexes, the so-called inflammasomes. Canonical inflammasomes are assembled by NOD-like receptor (NLR) or PYHIN family members and activate caspase-1, which promotes the induction of pyroptosis and the release of mature interleukin-1β/-18. Recently, a noncanonical inflammasome pathway was discovered that results in caspase-11 activation in response to bacterial lipopolysaccharide (LPS) in the cytosol. Interestingly, caspase-11 induces pyroptosis by itself, but requires NLRP3, the inflammasome adapter ASC, and caspase-1 to promote cytokine secretion. Here, we have studied the mechanism by which caspase-11 controls IL-1β secretion. Investigating NLRP3/ASC complex formation, we find that caspase-11 functions upstream of a canonical NLRP3 inflammasome. The activation of NLRP3 by caspase-11 during LPS transfection is a cell-intrinsic process and is independent of the release of danger signals. Furthermore, we show that active caspase-11 leads to a drop of intracellular potassium levels, which is necessary to activate NLRP3. Our study, therefore, sheds new light on the mechanism of noncanonical inflammasome signaling.

KEYWORDS:

Caspase-11; Inflammasome; Interleukin-1 beta (IL-1β); Lipopolysaccharide; NLRP3; Potassium efflux; Pyroptosis

PMID:
26173909
DOI:
10.1002/eji.201545772
[Indexed for MEDLINE]
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