Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4.

Nobuhiko Kayagaki, Michael T. Wong, Irma B. Stowe, Sree Ranjani Ramani, Lino C. Gonzalez, Sachiko Akashi-Takamura, Kensuke Miyake, Juan Zhang, Wyne P. Lee, Artur Muszyn´ ski, Lennart S. Forsberg, Russell W. Carlson, Vishva M. Dixit. Science. (2013) 341, 1246-124.

Speaker: Chen-Chu Kao (高禎鞠)                                        Time: 13:10~14:00, Dec. 18, 2013

Commentator: Dr. Chung-Hsin Tseng (曾忠信 老師)        Place: Room 601

Abstract:

Canonical inflammasome is a key cellular defense mechanism upon pathogen infection. Its  activation results in caspase-1 activation to promote the secretion of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and the inflammatory cell death called pyroptosis (1). Emerging evidence indicates that some Gram-negative bacterial infections also trigger “non-canonical inflammasome” that activate caspase-11, which is also implicated in pyroptosis (2). However, the underlying mechanism of activation of “non-canonical inflammasome” is still unclear. The current work demonstrates that delivery of E. coli LPS into the cytosol of macrophages activates caspase-11 and pyroptosis. This activation is independent of the known LPS receptor TLR4. Furthermore, LPS-mutant E. coli, which lacked mature hexa-acyl lipid A, failed to activate caspase-11. Importantly, the previous study indicates that loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of LPS (2). In accordance with these in vitro findings, wild-type and Tlr4-deficient mice succumb to a lethal dose of LPS when primed with the TLR3 agonist to induce pro-caspase-11 expression, while Casp11-deficient mice are protected from sepstic shock. This study shows that a novel cytoplasmic LPS detecting mechanism can trigger noncaninical inflammasome activation and then confer to sepsis. Nevertheless, the identity of the molecule(s) that detects cytosolic LPS and couples to caspase-11 activation remains unknown.

References:

1.    E. Latz, T. S. Xiao, A. Stutz, Activation and regulation of the inflammasomes. Nature reviews. Immunology 13, 397-411 (2013); published online EpubJun (10.1038/nri3452).

2.    N. Kayagaki, S. Warming, M. Lamkanfi, L. Vande Walle, S. Louie, J. Dong, K. Newton, Y. Qu, J. Liu, S. Heldens, J. Zhang, W. P. Lee, M. Roose-Girma, V. M. Dixit, Non-canonical inflammasome activation targets caspase-11. Nature 479, 117-121 (2011); published online EpubNov 3 (10.1038/nature10558).