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Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death.

Authors :
Dan Weng
Marty-Roix, Robyn
Ganesan, Sandhya
Proulx, Megan K.
Vladimer, Gregory I.
Kaiser, William J.
Mocarski, Edward S.
Pouliot, Kimberly
Francis Ka-Ming Chan
Kelliher, Michelle A.
Harris, Phillip A.
Bertin, John
Gough, Peter J.
Shayakhmetov, Dmitry M.
Goguen, Jon D.
Fitzgerald, Katherine A.
Silverman, Neal
Lien, Egil
Source :
Proceedings of the National Academy of Sciences of the United States of America; 5/20/2014, Vol. 111 Issue 20, p7391-7396, 6p
Publication Year :
2014

Abstract

A number of pathogens cause host cell death upon infection, and Yersinia pestis, infamous for its role in large pandemics such as the "Black Death" in medieval Europe, induces considerable cytotoxicity. The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effector Yersinia outer protein J (YopJ), is minimally affected by the absence of caspase-1, caspase- 11, Fas ligand, and TNF. Caspase-8 is known to mediate apoptotic death in response to infection with several viruses and to regulate programmed necrosis (necroptosis), but its role in bacterially induced cell death is poorly understood. Here we provide genetic evidence for a receptor-interacting protein (RIP) kinasecaspase- 8-dependent macrophage apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain- containing adapter-inducing interferon-β (TLR4-TRIF). Interestingly, macrophages lacking either RIP1, or caspase-8 and RIP3, also had reduced infection-induced production of IL-lβ, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-KB; and greatly compromised caspase-1 processing. Cleavage of the proform of caspase-1 is associated with triggering inflammasome activity, which leads to the maturation of IL-lβ and IL-18, cytokines important to host responses against Y. pestis and many other infectious agents. Our results identify a RIP1-caspase-8/RIP3-dependent caspase- 1 activation pathway after Y. pestis challenge. Mice defective in caspase-8 and RIP3 were also highly susceptible to infection and displayed reduced proinflammatory cytokines and myeloid cell death. We propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-κB and inflammasome activation, and host resistance after Y. pestis infection. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
111
Issue :
20
Database :
Complementary Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
96209786
Full Text :
https://doi.org/10.1073/pnas.1403477111