Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death
Marty-Roix, Robyn Lynn
Proulx, Megan K.
Vladimer, Gregory I.
Kaiser, William J.
Mocarski, Edward S.
Pouliot, Kimberly Lea
Chan, Francis Ka-Ming
Kelliher, Michelle A.
Harris, Phillip A.
Gough, Peter J.
Shayakhmetov, Dmitry M.
Goguen, Jon D.
Fitzgerald, Katherine A.
Silverman, Neal S.
Student AuthorsDan Weng
UMass Chan AffiliationsDepartment of Cancer Biology
Department of Microbiology and Physiological Systems
Department of Medicine, Division of Infectious Diseases and Immunology
Document TypeJournal Article
MetadataShow full item record
AbstractA 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) kinase-caspase-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-1β, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-κB; 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-1β 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.
Weng D, Marty-Roix R, Ganesan S, Proulx MK, Vladimer GI, Kaiser WJ, Mocarski ES, Pouliot K, Chan FK, Kelliher MA, Harris PA, Bertin J, Gough PJ, Shayakhmetov DM, Goguen JD, Fitzgerald KA, Silverman N, Lien E. Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. Proc Natl Acad Sci U S A. 2014 May 20;111(20):7391-6. doi: 10.1073/pnas.1403477111. Link to article on publisher's website
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33331
Related ResourcesLink to article in PubMed
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