Inflammatory caspases are innate immune receptors for intracellular LPS

Jianjin Shi, Yue Zhao, Yupeng Wang, Wenqing Gao, Jingjin Ding, Peng Li,       Liyan Hu & Feng Shao. Nature. (2014) 514, 187-192

Speaker: Chen-Chu Kao (高禎鞠)                                Place: Room 601

Commentator:Dr. Pei-Jane Tsai (蔡佩珍老師)            Time: 13:10~14:00, April 29, 2015

Abstract:

Septic shock syndrome is a widespread and uncontrolled inflammatory state resulting from a host systemic response to bacterial infection. Particularly, lipopolysaccharide (LPS) derived from Gram-negative bacteria plays a central role in sepsis/septic shock. TLR4 is known as the key pattern-recognition receptor for LPS-induced inflammatory responses. However, recent evidence revealed a TLR4-independent pathway in response to the delivery of LPS to the cytosol, in which caspase-11-mediated non-canonical inflammasome is critical for cytoplasmic LPS-induced inflammatory responses. Activation of caspase-11-mediated non-canonical inflammasome leads to two key downstream effector functions: activation of caspase-1 which in turn activates IL-1β and IL-18, and caspase-11-dependent pyroptosis, an inflammatory form of cell death (1, 2). However, the identity of cytosolic LPS sensors and the underlying mechanisms of caspase-11 activation remain unknown. This study shows that human caspase-4 and caspase-5 are orthologs of mouse caspase-11, which is required for LPS-induced pyroptosis in human monocytes, epithelial cells and keratinocytes. Furthermore, the specificity of LPS and lipid A binding by caspase-4/11 is mediated by the CARD domain. LPS binding induced oligomerization is required for caspase-4/11 activation. Together, this study identifies novel pattern recognition in caspase 4/11-dependent non-canonical inflammasome. In a clinical setting, antagonizing caspase-4 and -5, the humanorthologs of mouse caspase-11, might be the future direction of the treatment of LPS-induced sepsis.

References:

1.    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).

2.    N. Kayagaki, M. T. Wong, I. B. Stowe, S. R. Ramani, L. C. Gonzalez, S. Akashi-Takamura, K. Miyake, J. Zhang, W. P. Lee, A. Muszynski, L. S. Forsberg, R. W. Carlson, V. M. Dixit, Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246-1249 (2013); published online EpubSep 13 (10.1126/science.1240248).